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51. In Vitro Analysis of the Interaction between Atovaquone and Proguanil against Liver Stage Malaria Parasites

Author: Jean-François Franetich, Lídia Barata, Gigliola Zanghi, Pascal Houzé, Jérôme Clain, Dominique Mazier, Khadija Boutbibe, Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut de recherche pour le développement ( IRD [Burkina Faso] ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre National de Référence du Paludisme [CHU Pitié-Salpétrière], Centre National de Référence du Paludisme, PRES Sorbonne Paris Cité-APHP-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Institut de recherche pour le développement (IRD [Burkina Faso]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-PRES Sorbonne Paris Cité, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Drug, Cycloguanil, Proguanil, media_common.quotation_subject, Plasmodium falciparum, Pharmacology, 03 medical and health sciences, Antimalarials, Inhibitory Concentration 50, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, medicine, Humans, Pharmacology (medical), Malaria, Falciparum, Atovaquone, media_common, biology, Triazines, biology.organism_classification, medicine.disease, In vitro, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Combinations, 030104 developmental biology, Infectious Diseases, Liver, Hepatocytes, human activities, Plasmodium yoelii, Malaria, medicine.drug
Abstract: The interaction between atovaquone and proguanil has never been studied against liver stage malaria, which is the main target of this drug combination when used for chemoprevention. Using human hepatocytes lacking cytochrome P450 activity, and thus avoiding proguanil metabolizing into potent cycloguanil, we show in vitro that the atovaquone-proguanil combination synergistically inhibits the growth of rodent Plasmodium yoelii parasites. These results provide a pharmacological basis for the high efficacy of atovaquone-proguanil used as malaria chemoprevention.
Published: 2016
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52. Notch signaling in group 3 innate lymphoid cells modulates their plasticity

Author: James P. Di Santo, Sylvestre Chea, Ana Cumano, Thibaut Perchet, Thomas Verrier, Delphine Guy-Grand, Rachel Golub, Christian A. J. Vosshenrich, Maxime Petit, Elena Gaia Banchi, Cellule Pasteur, PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Pasteur Institute, INSERM, Université Paris Diderot, and the Ministère de la Recherche (to S.C. and T.V.), the Association pour la Recherche sur le Cancer (to S.C. and R.G.), the REVIVE Future Investment Program and the Agence Nationale de la Recherche (ANR) (grant 'Twothyme') (to A.C.), the Ligue Nationale contre le Cancer (to J.P.D.S. and T.V.), the ANR (grant 'Myeloten') (to R.G.), and the Institut National du Cancer (grant 'Role of the immune microenvironment during liver carcinogenesis') (to R.G.) and the Université Sorbonne Paris Cité (grant 'Mucocell'), ANR-14-CE11-0022,Twothyme,Deux progéniteurs hématopoïétiques différents établissent le compartiment de lymphocytes T: tester un nouveau paradigme du développement T.(2014), ANR-13-ISV1-0003,MYELOTEN,DEREGULATION DE L'HEMATOPOIESE PAR LA SUREXPRESSION DE L'INTERLEUKINE-10 : IMPLICATIONS DANS LE DEVELOPPEMENT DE PATHOLOGIES HEMATOLOGIQUES(2013), Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée - Innate Immunity, and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, viruses, Population, Notch signaling pathway, Biology, Cell fate determination, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Transforming Growth Factor beta, Animals, Humans, Cell Lineage, Lymphocytes, education, Molecular Biology, Transcription factor, Cells, Cultured, Cell Proliferation, Mice, Knockout, education.field_of_study, Innate immune system, Receptors, Notch, Effector, Interleukins, Innate lymphoid cell, virus diseases, Cell Biology, Aryl hydrocarbon receptor, Immunity, Innate, Cell biology, Intestines, 030104 developmental biology, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, 030215 immunology, Signal Transduction
Abstract: International audience; The Notch signaling pathway is conserved throughout evolution, and it controls various processes, including cell fate determination, differentiation, and proliferation. Innate lymphoid cells (ILCs) are lymphoid cells lacking antigen receptors that fulfill effector and regulatory functions in innate immunity and tissue remodeling. Type 3 ILCs (ILC3s) reinforce the epithelial barrier and maintain homeostasis with intestinal microbiota. We demonstrated that the population of natural cytotoxicity receptor-positive (NCR(+)) ILC3s in mice is composed of two subsets that have distinct developmental requirements. A major subset depended on the activation of Notch2 in NCR(-) ILC3 precursors in the lamina propria of the small intestine to stimulate expression of the genes encoding the transcription factors T-bet, RORγt, and aryl hydrocarbon receptor (AhR). Notch signaling contributed to the transition of NCR(-) cells into NCR(+) cells, the more proinflammatory subset, in a cell-autonomous manner. In the absence of Notch signaling, this subset of NCR(-) ILC3s did not acquire the gene expression profile of NCR(+) ILC3s. A second subset of NCR(+) ILC3s did not depend on Notch for their development or for increased transcription factor abundance; however, their production of cytokines and cell surface abundance of NCRs were decreased in the absence of Notch signaling. Together, our data suggest that Notch is a regulator of the plasticity of ILC3s by controlling NCR(+) cell fate.
Published: 2016
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53. The Regulatory Networks That Control Clostridium difficile Toxin Synthesis

Author: Johann Peltier, Bruno Dupuy, Isabelle Martin-Verstraete, Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Cellule Pasteur, PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Publishing costs and research in the authors’ lab were funded by the Institut Pasteur and a research grant (AI057637) from the US Public Health service., Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), and Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité
Subjects: 0301 basic medicine, Catabolite Repression, toxin regulation, sporulation, MESH: Bacterial Toxins/genetics, Proline, PaLoc, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], 030106 microbiology, Bacterial Toxins, lcsh:Medicine, Clostridium difficile toxin A, Review, Biology, Gut flora, Toxicology, medicine.disease_cause, Microbiology, Clostridia, MESH: Catabolite Repression, 03 medical and health sciences, Sigma factor, medicine, MESH: Clostridium difficile/metabolism, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Cysteine, MESH: Transcription Factors/genetics, MESH: Cysteine/metabolism, Toxin, Clostridioides difficile, lcsh:R, MESH: Bacterial Toxins/biosynthesis, quorum sensing, stress signals, c-di-GMP, Clostridium difficile, biology.organism_classification, 3. Good health, Quorum sensing, C. difficile, growth phase, MESH: Proline/metabolism, MESH: Clostridium difficile/genetics, Bacteria, carbon catabolite repression system, Transcription Factors
Abstract: International audience; The pathogenic clostridia cause many human and animal diseases, which typically arise as a consequence of the production of potent exotoxins. Among the enterotoxic clostridia, Clostridium difficile is the main causative agent of nosocomial intestinal infections in adults with a compromised gut microbiota caused by antibiotic treatment. The symptoms of C. difficile infection are essentially caused by the production of two exotoxins: TcdA and TcdB. Moreover, for severe forms of disease, the spectrum of diseases caused by C. difficile has also been correlated to the levels of toxins that are produced during host infection. This observation strengthened the idea that the regulation of toxin synthesis is an important part of C. difficile pathogenesis. This review summarizes our current knowledge about the regulators and sigma factors that have been reported to control toxin gene expression in response to several environmental signals and stresses, including the availability of certain carbon sources and amino acids, or to signaling molecules, such as the autoinducing peptides of quorum sensing systems. The overlapping regulation of key metabolic pathways and toxin synthesis strongly suggests that toxin production is a complex response that is triggered by bacteria in response to particular states of nutrient availability during infection.
Published: 2016
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54. Les évolutions de l’activité de la hiérarchie paramédicale en lien avec la nouvelle gouvernance hospitalière

Author: Bercot, Régine, Waelli, Mathias, Genre, Travail, Mobilités (GTM), Centre de recherches sociologiques et politiques de Paris (CRESPPA), Centre National de la Recherche Scientifique (CNRS)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN), École des Hautes Études en Santé Publique [EHESP] (EHESP), EA Management des Organisations de Santé (EA MOS), PRES Sorbonne Paris Cité-École des Hautes Études en Santé Publique [EHESP] (EHESP), ARAMOS - IRTS- KNEDGE, KEDGE Business School, les IRTS PACA-Corse et Aquitaine, Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), École des Hautes Études en Santé Publique [EHESP] (EHESP)-PRES Sorbonne Paris Cité, Institut du Management (IDM), Genre, Travail, Mobilités (Cresppa-GTM), and Université Paris Nanterre (UPN)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Nanterre (UPN)-Université Paris 8 Vincennes-Saint-Denis (UP8)-Centre National de la Recherche Scientifique (CNRS)
Subjects: négociation, [SHS.SOCIO]Humanities and Social Sciences/Sociology, gouvernance, hôpital, cadre supérieur de soin, cadre paramédical de pôle, [SHS]Humanities and Social Sciences
Abstract: International audience; La création des pôles au sein des hôpitaux s'est traduit par la mise en place de nouvelles fonctions intermédiaires, décentralisant ainsi pour partie certaines dimensions du management. Cet article vise à rendre compte de la place juridique des Cadres paramédicaux médicaux. Nouveau métier inscrit dans la hiérarchie paramédicale, il est peu connu et encore mal valorisé. Dans ce contexte, notre objectif est de donner consistance à l’activité de ces cadres paramédicaux de pôle, en nous préoccupant de leur activité de travail. Ceci afin de rendre compte de leur action sur le fonctionnement des pôles.Qui sont les CPP ? Quelle est la nature de leur activité ? Quel est l’impact de cette activité sur le fonctionnement des pôles ? Quelle place occupent-ils ? L’argumentation prend appui sur des études de cas réalisées dans une organisation spécifique, dont la dimension bureaucratique renforcée pèse particulièrement sur l’activité et contribue encore davantage à occulter la dimension politique du travail des cadres. Dans un premier temps nous présenterons la méthode et nous reviendrons sur notre choix de rester sur les terrains parisiens pour cette communication qui explore le développement de l’activité des CPP. Dans un second temps, nous présenterons nos premiers résultats en nous centrant sur les modalités de collaboration au sein des pôles et avec les autres acteurs de l’hôpital. Ces données révèlent la forte dimension politique de l’activité du CPP, contrairement à la perception véhiculée par une vision médico centrée de la gestion des pôle.
Published: 2016

55. Mother-to-Child Transmission of HTLV-1 Epidemiological Aspects, Mechanisms and Determinants of Mother-to-Child Transmission

Author: Antoine Gessain, Aurore Vidy-Roche, Sandra Martin-Latil, Philippe V. Afonso, Pierre-Emmanuel Ceccaldi, Patricia Jeannin, Florent Percher, Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Virus Entériques, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), The authors thank Florence Buseyne, Olivier Cassar and Catherine Cecilio for helpful advices and improvement of the manuscript. Florent Percher is a recipient of a DIM Malinf (Région Ile de France) Ph.D. fellowship. Part of this work is financially supported by the Ligue contre le Cancer, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7)
Subjects: 0301 basic medicine, Male, breastfeeding, viruses, [SDV]Life Sciences [q-bio], Breastfeeding, lcsh:QR1-502, Review, lcsh:Microbiology, Myelopathy, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Tropical spastic paraparesis, Human T-lymphotropic virus 1, MESH: Middle Aged, biology, Transmission (medicine), Antibody titer, virus diseases, 3. Good health, retrovirus, Infectious Diseases, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Acute Disease, Female, Adult, 03 medical and health sciences, MESH: Infectious Mononucleosis, Virology, medicine, Humans, human, MESH: Anemia, Hemolytic, MESH: Humans, business.industry, Infant, MESH: Adult, medicine.disease, biology.organism_classification, HTLV-I Infections, Infectious Disease Transmission, Vertical, intestinal barrier, 030104 developmental biology, HTLV-1, Immunology, Etiology, business, Breast feeding, MESH: Female
Abstract: International audience; Human T-cell Lymphotropic Virus type 1 (HTLV-1) is a human retrovirus that infects at least 5–10 million people worldwide, and is the etiological agent of a lymphoproliferative malignancy; Adult T-cell Leukemia/Lymphoma (ATLL); and a chronic neuromyelopathy, HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), as well as other inflammatory diseases such as infective dermatitis and uveitis. Besides sexual intercourse and intravenous transmission, HTLV-1 can also be transmitted from infected mother to child during prolonged breastfeeding. Some characteristics that are linked to mother-to-child transmission (MTCT) of HTLV-1, such as the role of proviral load, antibody titer of the infected mother, and duration of breastfeeding, have been elucidated; however, most of the mechanisms underlying HTLV-1 transmission during breast feeding remain largely unknown, such as the sites of infection and cellular targets as well as the role of milk factors. The present review focuses on the latest findings and current opinions and perspectives on MTCT of HTLV-1.
Published: 2016
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56. Analysis of repair mechanisms following an induced double-strand break uncovers recessive deleterious alleles in the candida albicans diploid genome

Author: Natacha Sertour, Gavin Sherlock, Adeline Feri, Corinne Maufrais, Katja Schwartz, Pierre-Henri Commere, Mélanie Legrand, Raphaël Loll-Krippleber, Christophe d'Enfert, Marie-Elisabeth Bougnoux, D'Enfert, Christophe, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), Cytométrie (Plate-forme), Institut Pasteur [Paris] (IP), Centre d'Informatique pour la Biologie, Stanford University, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work, including the efforts of Gavin Sherlock, was funded by HHS |National Institutes of Health (NIH) (R01-AI077737 and R01-DE015873).This work, including the efforts of Adeline Feri, was funded by InstitutPasteur. This work, including the efforts of Adeline Feri, was funded byInstitut National de la Recherche Agronomique (INRA)., Biologie et Pathogénicité fongiques, Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Institut Pasteur [Paris], PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris], and Stanford University [Stanford]
Subjects: 0301 basic medicine, polymorphisme nucléotidique simple (SNP), Mitotic crossover, DNA Repair, [SDV]Life Sciences [q-bio], 030106 microbiology, Loss of Heterozygosity, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Microbiology, Loss of heterozygosity, 03 medical and health sciences, analyse de génome, Virology, Genome stability, Humans, DNA Breaks, Double-Stranded, Allele, Candida albicans, Gene, Alleles, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Recombination, Genetic, Genetics, DNA DSB repair, [SDV.GEN]Life Sciences [q-bio]/Genetics, I-SceI meganuclease, Haplotype, recessive lethal allele, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, biology.organism_classification, QR1-502, Corpus albicans, 030104 developmental biology, candida albicans, Genome, Fungal, séquençage de gènes, Research Article
Abstract: The diploid genome of the yeast Candida albicans is highly plastic, exhibiting frequent loss-of-heterozygosity (LOH) events. To provide a deeper understanding of the mechanisms leading to LOH, we investigated the repair of a unique DNA double-strand break (DSB) in the laboratory C. albicans SC5314 strain using the I-SceI meganuclease. Upon I-SceI induction, we detected a strong increase in the frequency of LOH events at an I-SceI target locus positioned on chromosome 4 (Chr4), including events spreading from this locus to the proximal telomere. Characterization of the repair events by single nucleotide polymorphism (SNP) typing and whole-genome sequencing revealed a predominance of gene conversions, but we also observed mitotic crossover or break-induced replication events, as well as combinations of independent events. Importantly, progeny that had undergone homozygosis of part or all of Chr4 haplotype B (Chr4B) were inviable. Mining of genome sequencing data for 155 C. albicans isolates allowed the identification of a recessive lethal allele in the GPI16 gene on Chr4B unique to C. albicans strain SC5314 which is responsible for this inviability. Additional recessive lethal or deleterious alleles were identified in the genomes of strain SC5314 and two clinical isolates. Our results demonstrate that recessive lethal alleles in the genomes of C. albicans isolates prevent the occurrence of specific extended LOH events. While these and other recessive lethal and deleterious alleles are likely to accumulate in C. albicans due to clonal reproduction, their occurrence may in turn promote the maintenance of corresponding nondeleterious alleles and, consequently, heterozygosity in the C. albicans species., IMPORTANCE Recessive lethal alleles impose significant constraints on the biology of diploid organisms. Using a combination of an I-SceI meganuclease-mediated DNA DSB, a fluorescence-activated cell sorter (FACS)-optimized reporter of LOH, and a compendium of 155 genome sequences, we were able to unmask and identify recessive lethal and deleterious alleles in isolates of Candida albicans, a diploid yeast and the major fungal pathogen of humans. Accumulation of recessive deleterious mutations upon clonal reproduction of C. albicans could contribute to the maintenance of heterozygosity despite the high frequency of LOH events in this species.
Published: 2016
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57. In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

Author: Estelle Robidel, Laure Fournier, Gwennhael Autret, Philippe Halimi, Paule Bénit, Sébastien Fontaine, Bertrand Tavitian, Alexandre Bellucci, Charlotte Lussey-Lepoutre, Maxime Janin, Chris Ottolenghi, Nelly Burnichon, Benjamin Banting, Judith Favier, Alexandre Buffet, Aurélie Morin, Franck Zinzindohoue, Anne-Paule Gimenez-Roqueplo, Laurence Amar, Charles-André Cuénod, Pierre Rustin, Tavitian, Bertrand, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine [Université Paris Diderot - Paris 7], Université Paris Diderot - Paris 7 (UPD7), This work received funding from the Cancer Research for Personalized Medicine - CARPEM project (Site de Recherche Intégré sur le Cancer - SIRIC), the Agence Nationale de la Recherche (ANR-2011-JCJC-00701 MODEOMAPP), the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 259735, the Institut National du Cancer et la Direction Générale de l’Offre de Soins (INCa-DGOS_8663) for the COMETE network., Service d'hypertension artérielle et médecine vasculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie Métabolique, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de radiologie cardio-vasculaire [CHU HEGP], This work received funding from the Cancer Research for Personalized Medicine - CARPEMproject (Site de Recherche Intégré sur le Cancer- SIRIC), the Agence Nationale de la Recherche (ANR-2011-JCJC-00701MODEOMAPP), the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259735, the Institut National du Cancer et la Direction Générale de l'Offre de Soins (INCa-DGOS_8663) for the COMETE network., ANR-11-JSV1-0007,MODEOMAPP,Décryptage moléculaire de la malignité dans le phéochromocytome et paragangliome(2011), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-AP-HP Hôpital européen Georges-Pompidou (Paris), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), ANR : ANR-2001-JCJC-00701-MODEOMAPP, Autret, Gwennhael, Jeunes Chercheuses et Jeunes Chercheurs - Décryptage moléculaire de la malignité dans le phéochromocytome et paragangliome - - MODEOMAPP2011 - ANR-11-JSV1-0007 - JCJC - VALID, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Hôpital Européen Georges Pompidou [APHP] (HEGP)
Subjects: 0301 basic medicine, Male, Cancer Research, Pathology, medicine.medical_specialty, Succinate, SDHB, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Succinic Acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gene mutation, Biology, medicine.disease_cause, Pheochromocytoma, 03 medical and health sciences, Mice, paraganglioma, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Paraganglioma, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, SDHA Gene Mutation, medicine, Animals, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Succinate dehydrogenase, Electron Transport Complex II, Membrane Proteins, imaging, medicine.disease, Xenograft Model Antitumor Assays, pheochromocytoma, magnetic resonance spectroscopy, 3. Good health, Succinate Dehydrogenase, 030104 developmental biology, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Purpose: Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy. Experimental Design: A pulsed proton magnetic resonance spectroscopy (1H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb−/− or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors. Results: A succinate peak was observed at 2.44 ppm by 1H-MRS in all Sdhb−/−-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, 1H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene. Conclusions: Detection of succinate by 1H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors. Clin Cancer Res; 22(5); 1120–9. ©2015 AACR.
Published: 2016
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58. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma

Author: Sandrine Imbeaud, Yannick Ladeiro, Julien Calderaro, Laura Pelletier, Françoise Degos, Eric Chevet, Charles Balabaud, Fabien Calvo, Eric Letouzé, Alexis Laurent, Paulette Bioulac-Sage, Giuliana Amaddeo, Mélanie Letexier, Jessica Zucman-Rossi, Cécile Guichard, Gabrielle Couchy, Bruno Clément, Ichrafe Ben Maad, Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Labex Immuno-oncology, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Service de Pathologie [Créteil], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Henri Mondor, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), IntegraGen SA, Service d'hépatologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Beaujon, Microenvironnement et remodelage, Foie, métabolismes et cancer, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de chirurgie digestive, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Cartes d'Identité des Tumeurs ( CIT ), Ligue Nationale Contre le Cancer (LNCC), Institut National du Cancer [Boulogne Billancourt] ( INC ), Service d'Hépato-Gastro Entérologie et Oncologie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), This work was supported by the INCa with the ICGC project, the Ligue Nationale Contre le Cancer ('Cartes d'identité des tumeurs' program), the PAIR-CHC project NoFLIC (funded by INCa and Association pour la recherche contre le Cancer, ARC), the Réseau national CRB Foie and BioIntelligence. C.G., G.A., are supported by a fellowship from the INCa and ANRS respectively., Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Cartes d'Identité des Tumeurs (CIT), Institut National du Cancer [Boulogne Billancourt] (INC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Genetics, 0303 health sciences, Mutation, Oncogene, ARID1A, Tumor suppressor gene, Somatic cell, Wnt signaling pathway, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Biology, medicine.disease, medicine.disease_cause, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, medicine, Cancer research, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Gene, 030304 developmental biology
Abstract: International audience; Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/β-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides insight into the somatic mutational landscape in HCC and identifies interactions between mutations in oncogene and tumor suppressor gene mutations related to specific risk factors.
Published: 2012
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59. Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain

Author: Julien Pansiot, Raffaella Moretti, Philippe Bonnin, Lorena Di Criscio, Zsolt Csaba, Olivier Baud, Luigi Titomanlio, Christiane Charriaut-Marlangue, Valérie C. Besson, Pierre-Louis Leger, A. Gentili, Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Clinica Pediatrica – Ospedale di Udine, Università degli Studi di Udine - University of Udine [Italie], Service de réanimation néonatale et pédiatrique, CHU Trousseau [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Pharmacologie de la circulation cérébrale ( EA 4475 ), Université Paris Descartes - Paris 5 ( UPD5 ), AP-HP, Hôpital Robert Debré, Pôle de Pédiatrie Aiguë et Médecine Interne, Service d'Accueil des Urgences Pédiatriques, Université Paris Diderot - Paris 7 ( UPD7 ), Carcinose Angiogenèse et Recherche Translationnelle, Angiogenese et recherche translationnelle ( CART U965 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiologie Clinique, Explorations-Fonctionnelles, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Réanimation et Pédiatrie Néonatales, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), INSERM, Charriaut-Marlangue, Christiane, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de réanimation néonatale et pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Pharmacologie de la circulation cérébrale (EA 4475), Université Paris Descartes - Paris 5 (UPD5), Université Paris Diderot - Paris 7 (UPD7), Angiogenese et recherche translationnelle (CART U965), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)
Subjects: 0301 basic medicine, Phosphodiesterase Inhibitors, Pharmacology, Polymerase Chain Reaction, Brain Ischemia, Brain ischemia, chemistry.chemical_compound, Mice, 0302 clinical medicine, M2 microglia, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Stroke, Focal ischemia, ddc:618, Cerebral infarction, General Neuroscience, Penumbra, Immunohistochemistry, 3. Good health, Neurology, Anesthesia, cardiovascular system, Microglia, medicine.symptom, Phosphodiesterase Inhibitors/pharmacology, Sildenafil, Immunology, Ischemia, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Neonatal mice, Microglia/drug effects/enzymology, Sildenafil Citrate, Lesion, 03 medical and health sciences, Cellular and Molecular Neuroscience, Brain Ischemia/enzymology/pathology, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Animals, cardiovascular diseases, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Neuroinflammation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, business.industry, Research, Microcirculation, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, chemistry, Animals, Newborn, business, 030217 neurology & neurosurgery, Sildenafil Citrate/pharmacology
Abstract: Background Perinatal ischemic stroke is the most frequent form of cerebral infarction in neonates; however, evidence-based treatments are currently lacking. We have previously demonstrated a beneficial effect of sildenafil citrate, a PDE-5 inhibitor, on stroke lesion size in neonatal rat pups. The present study investigated the effects of sildenafil in a neonatal mouse stroke model on (1) hemodynamic changes and (2) regulation of astrocyte/microglia-mediated neuroinflammation. Methods Ischemia was induced in C57Bl/6 mice on postnatal (P) day 9 by permanent middle cerebral artery occlusion (pMCAo), and followed by either PBS or sildenafil intraperitoneal (i.p.) injections. Blood flow (BF) velocities were measured by ultrasound imaging with sequential Doppler recordings and laser speckle contrast imaging. Animals were euthanized, and brain tissues were obtained at 72 h or 8 days after pMCAo. Expression of M1- and M2-like microglia/macrophage markers were analyzed. Results Although sildenafil (10 mg/kg) treatment potently increased cGMP concentrations, it did not influence early collateral recruitment nor did it reduce mean infarct volumes 72 h after pMCAo. Nevertheless, it provided a significant dose-dependent reduction of mean lesion extent 8 days after pMCAo. Suggesting a mechanism involving modulation of the inflammatory response, sildenafil significantly decreased microglial density at 72 h and 8 days after pMCAo. Gene expression profiles indicated that sildenafil treatment also modulates M1- (ptgs2, CD32 and CD86) and M2-like (CD206, Arg-1 and Lgals3) microglia/macrophages in the late phase after pMCAo. Accordingly, the number of COX-2+ microglia/macrophages significantly increased in the penumbra at 72 h after pMCAo but was significantly decreased 8 days after ischemia in sildenafil-treated animals. Conclusions Our findings argue that anti-inflammatory effects of sildenafil may provide protection against lesion extension in the late phase after pMCAo in neonatal mice. We propose that sildenafil treatment could represent a potential strategy for neonatal ischemic stroke treatment/recovery. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0560-4) contains supplementary material, which is available to authorized users.
Published: 2015
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60. Prevalence of gastrointestinal symptoms in patients with influenza, clinical significance, and pathophysiology of human influenza viruses in faecal samples: what do we know?

Author: Sylvie van der Werf, Thomas Hanslik, Thierry Blanchon, Alessandra Falchi, Pierre-Emmanuel Ceccaldi, Rémi N. Charrel, Laëtitia Minodier, Laboratoire de Virologie, Université Pascal Paoli (UPP), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence des virus influenzae (Grippe) (CNR), Institut Pasteur [Paris], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Médecine Interne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Centre National de Référence des virus influenzae (Grippe)-Génétique moléculaire des virus à ARN (CNR), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)
Subjects: Gastrointestinal Diseases, Human influenza, Orthomyxoviridae, Review, Biology, Gastrointestinal symptoms, Virus, Feces, Respiratory infection, Virology, Influenza, Human, Prevalence, Humans, Clinical significance, Transmission (medicine), virus diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, biology.organism_classification, Influenza, Pathophysiology, Intestine, 3. Good health, Intestines, Infectious Diseases, Stool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, RNA, Seasons
Abstract: This review provides for the first time an assessment of the current understanding about the occurrence and the clinical significance of gastrointestinal (GI) symptoms in influenza patients, and their correlation with the presence of human influenza viruses in stools of patients with confirmed influenza virus infection. Studies exploring how human influenza viruses spread to the patient’s GI tract after a primary respiratory infection have been summarized. We conducted a systematic search of published peer-reviewed literature up to June 2015 with regard to the above-mentioned aspects, focusing on human influenza viruses (A(H1N1), A(H1N1)pdm09, A(H3N2), and B). Forty-four studies were included in this systematic review and meta-analysis. The pooled prevalence of any digestive symptoms ranged from 30.9 % (95 % CI, 9.8 to 57.5; I2 = 97.5 %) for A(H1N1)pdm09 to 2.8 % (95 % CI, 0.6 to 6.5; I2 = 75.4 %) for A(H1N1). The pooled prevalence of influenza viruses in stool was 20.6 % (95 % CI, 8.9 to 35.5; I2 = 96.8 %), but their correlation with GI symptoms has rarely been explored. The presence of viral RNA in stools because of haematogenous dissemination to organs via infected lymphocytes is likely, but the potential to cause direct intestinal infection and faecal–oral transmission warrants further investigation. This review highlights the gaps in our knowledge, and the high degree of uncertainty about the prevalence and significance of GI symptoms in patients with influenza and their correlation with viral RNA positivity in stool because of the high level of heterogeneity among studies. Electronic supplementary material The online version of this article (doi:10.1186/s12985-015-0448-4) contains supplementary material, which is available to authorized users.
Published: 2015
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61. Relationship between early language skills and the development of inattention/hyperactivity symptoms during the preschool period: Results of the EDEN mother-child cohort

Author: Jonathan Bernard, Franck Ramus, Hugo Peyre, Regis HANKARD, Blandine De Lauzon-Guillain, CEDRIC GALERA, Xavier FRITEL, Marie-Josephe Saurel-Cubizolles, Johanna Lepeule, Barbara Heude, Judith Van der Waerden, Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS), Epidemiologie-Biostatistique [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Psychiatrie de l'enfant et de l'adolescent [CH C. Perrens, Bordeaux], SECOP - centre hospitalier Charles Perrens, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Hôpital Corentin Celton [Issy-les-Moulineaux], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 6 : ORCHAD - Origines précoces de la santé du développement de l'enfant (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-10-IDEX-0001-02/10-LABX-0087,IEC,Institute of Cognitive Studies of Ecole normale superieure(2010), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Hôpital Corentin Celton [Issy-les-Moulineaux], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Psychiatrie et Neurosciences (U894), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), BMC, BMC, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Laboratoire de sciences cognitives et psycholinguistique ( LSCP ), Département d'Etudes Cognitives - ENS Paris ( DEC ), École normale supérieure - Paris ( ENS Paris ) -École normale supérieure - Paris ( ENS Paris ) -École des hautes études en sciences sociales ( EHESS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bordeaux Ségalen [Bordeaux 2], Institut Pierre Louis d'Epidémiologie et de Santé Publique ( iPLESP ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-Hôpitaux Universitaires Paris Ouest - Hôpital Corentin Celton [Issy-les-Moulineaux], Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Equipe 6 : ORCHAD - Origines précoces de la santé du développement de l'enfant ( CRESS - U1153 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and ANR-10-IDEX-0001-02/10-LABX-0087,IEC,Institute of Cognitive Studies of Ecole normale superieure ( 2010 )
Subjects: Male, [SDV]Life Sciences [q-bio], education, Child Behavior, Hyperkinesis, Language Development, Structural equation modeling, Developmental psychology, 03 medical and health sciences, 0302 clinical medicine, Humans, ADHD, 0501 psychology and cognitive sciences, Child, Preschool, Early language, Language, Schools, [ SDV ] Life Sciences [q-bio], 4. Education, 05 social sciences, Mother-Child Relations, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Language development, Attention Deficit Disorder with Hyperactivity, Child, Preschool, Cohort, Female, Psychology, 030217 neurology & neurosurgery, Period (music), Research Article, 050104 developmental & child psychology
Abstract: Background This study aims to examine bidirectional relationships between children’s language skills and Inattention/Hyperactivity (IH) symptoms during preschool. Method Children (N = 1459) from the EDEN mother-child cohort were assessed at ages 3 and 5.5 years. Language skills were evaluated using the WPPSI-III, NEPSY and ELOLA batteries. Children’s behavior, including IH symptoms, was assessed using the parent-rated Strengths & Difficulties Questionnaire (SDQ). Using a Structural Equation Modeling (SEM) approach, we examined the relationship between language skills and IH symptoms, as well as potential mediating processes. Results SEM analyses indicated a small negative effect of language skills at 3 years on ADHD symptoms at 5.5 years after adjusting for IH symptoms at 3 years (β =−0.12, SE = 0.04, p-value = 0.002). Interpersonal difficulties did not mediate the relationship between early language skills and later IH symptoms, nor was this association reduced after adjusting for a broad range of pre- and postnatal environmental factors and performance IQ. Among different language skills, receptive syntax at 3 years was most strongly related to IH symptoms at 5.5 years. Conclusions Poor language skills at age 3 may predict IH symptoms when a child enters primary school. Implications for the understanding and the prevention of the co-occurrence of language disorders and ADHD are discussed. Electronic supplementary material The online version of this article (doi:10.1186/s12888-016-1091-3) contains supplementary material, which is available to authorized users.
Published: 2015
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62. Potent neutralizing antibodies in humans infected with zoonotic simian foamy viruses target conserved epitopes located in the dimorphic domain of the surface envelope protein

Author: Augustin Mouinga-Ondémé, Dirk Lindemann, Joelle Tobaly-Tapiero, Richard Njouom, Antoine Gessain, Caroline Lambert, Réjane Rua, Florence Buseyne, Julie Gouzil, Léa Richard, Edouard Betsem, Mathilde Couteaudier, Thomas Montange, Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institute of Virology [Dresden], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centre Pasteur du Cameroun, Réseau International des Instituts Pasteur (RIIP), Centre International de Recherches Médicales de Franceville (CIRMF), CL was personally supported by a doctoral grant from the French government program Investissement d'Avenir, Laboratory of Excellence, Integrative Biology of Emerging Infectious Diseases (LabEx IBEID, http://www.agence-nationale-recherche.fr/ProjetIA-10-LABX-0062). LR was personally supported by the Bourse de l’Ecole Normale Supérieure, Faculté Paris Diderot, http://www.ens.fr/. This work was supported by the Institut Pasteur in Paris, France, the Programme Transversal de Recherche from the Institut Pasteur [PTR#437], https://www.pasteur.fr/fr, and the Agence Nationale de la Recherche [grant ANR-10-LABX-62-IBEID, REEMFOAMY project, ANR 15-CE-15-0008-01, We thank P. Souque, C. Blanc, and P. Afonso for their helpful advice on the molecular biology experiments. We are indebted to Pascale Lesage, Alessia Zamborlini, Ali Saïb, and Olivier Schwartz for helpful discussions. We thank members from the EPVO research unit for discussions and technical advices., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-15-CE15-0008,REEMFOAMY,L'infection humaine par les virus foamy simiens zoonotiques : rôle des facteurs virologiques et immunologiques dans la restrcition de l'emergence virale(2015), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Dresden (TUD), Centre international de recherches médicales de Franceville (CIRMF), Organisation Mondiale de la Santé (OMS), and ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010)
Subjects: Male, 0301 basic medicine, Physiology, viruses, Artificial Gene Amplification and Extension, Disease Vectors, Blood plasma, Simian, Biochemistry, Epitope, Neutralization, Epitopes, Viral Envelope Proteins, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immune Physiology, Zoonoses, Medicine and Health Sciences, Viral replication, lcsh:QH301-705.5, Mammals, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, education.field_of_study, Immune System Proteins, Eukaryota, virus diseases, Hominidae, Middle Aged, Body Fluids, Polymerase chain reaction, 3. Good health, Blood, Infectious Diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Vertebrates, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Apes, Anatomy, Antibody, Research Article, Primates, Adult, lcsh:Immunologic diseases. Allergy, Gorillas, Pan troglodytes, Immunology, Population, Biology, Research and Analysis Methods, Microbiology, Antibodies, Viral vector, 03 medical and health sciences, Simian foamy virus, Virology, Genetics, Animals, Humans, Amino Acid Sequence, Chimpanzees, Molecular Biology Techniques, education, Molecular Biology, Gene, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Binding Sites, Gorilla gorilla, Co-infections, Organisms, Biology and Life Sciences, Proteins, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Antibodies, Neutralizing, 030104 developmental biology, lcsh:Biology (General), Amniotes, biology.protein, Parasitology, lcsh:RC581-607, Retroviridae Infections
Abstract: Human diseases of zoonotic origin are a major public health problem. Simian foamy viruses (SFVs) are complex retroviruses which are currently spilling over to humans. Replication-competent SFVs persist over the lifetime of their human hosts, without spreading to secondary hosts, suggesting the presence of efficient immune control. Accordingly, we aimed to perform an in-depth characterization of neutralizing antibodies raised by humans infected with a zoonotic SFV. We quantified the neutralizing capacity of plasma samples from 58 SFV-infected hunters against primary zoonotic gorilla and chimpanzee SFV strains, and laboratory-adapted chimpanzee SFV. The genotype of the strain infecting each hunter was identified by direct sequencing of the env gene amplified from the buffy coat with genotype-specific primers. Foamy virus vector particles (FVV) enveloped by wild-type and chimeric gorilla SFV were used to map the envelope region targeted by antibodies. Here, we showed high titers of neutralizing antibodies in the plasma of most SFV-infected individuals. Neutralizing antibodies target the dimorphic portion of the envelope protein surface domain. Epitopes recognized by neutralizing antibodies have been conserved during the cospeciation of SFV with their nonhuman primate host. Greater neutralization breadth in plasma samples of SFV-infected humans was statistically associated with smaller SFV-related hematological changes. The neutralization patterns provide evidence for persistent expression of viral proteins and a high prevalence of coinfection. In conclusion, neutralizing antibodies raised against zoonotic SFV target immunodominant and conserved epitopes located in the receptor binding domain. These properties support their potential role in restricting the spread of SFV in the human population., Author summary Foamy viruses are the oldest known retroviruses and have been mostly described to be nonpathogenic in their natural animal hosts. Simian foamy viruses (SFVs) can be transmitted to humans, in whom they establish persistent infection, as have the simian lenti- and deltaviruses that led to the emergence of two major human pathogens, human immunodeficiency virus type 1 (HIV-1) and human T lymphotropic virus type 1 (HTLV-1). Such cross-species transmission of SFV is ongoing in many parts of the world where humans have contact with nonhuman primates. We present the first comprehensive study of neutralizing antibodies in SFV-infected humans. We showed high titers of neutralizing antibodies in the plasma of most SFV-infected individuals. Neutralizing antibodies target the dimorphic portion of the envelope protein surface domain that overlap with the receptor binding domain. SFV-specific antibodies target epitopes conserved over 8 million years of co-speciation with their nonhuman primate host. Greater neutralization potency in infected individuals was statistically associated with smaller SFV-related hematological changes. In conclusion, our results suggest the protective action of neutralizing antibodies against SFV infection and spread in the human population.
Published: 2018
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63. Assessment of the frequency of sperm annulus defects in a large cohort of patients presenting asthenozoospermia

Author: Dirami, Thassadite, Rode, Baptiste, Wolf, Jean-Philippe, Gacon, Gérard, Dulioust, Emmanuel, Touré, Aminata, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université Paris Descartes and Agence Nationale de la Recherche (ANR-07-JCJC-0099, ANR-12-BSV1-0011-01 MUCOFERTIL), ANR-07-JCJC-0099,TAT1/SLC26A8,Study of the anion transporter TAT1 (SLC26A8) in sperm terminal differentiation and human male infertility(2007), ANR-12-BSV1-0011,MUCOFERTIL,La protéine TAT1 (SLC26A8), partenaire et activateur de CFTR dans le spermatozoïde, au carrefour des infertilités masculines et de la mucoviscidose.(2012), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5) - PRES Sorbonne Paris Cité - AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], ANR-07-JCJC-0099, JCJC, Study of the anion transporter TAT1 (SLC26A8) in sperm terminal differentiation and human male infertility(2007), ANR-12-BSV1-0011, MUCOFERTIL, La protéine TAT1 (SLC26A8), partenaire et activateur de CFTR dans le spermatozoïde, au carrefour des infertilités masculines et de la mucoviscidose.(2012), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bos, Mireille, Jeunes chercheuses & jeunes chercheurs - Study of the anion transporter TAT1 (SLC26A8) in sperm terminal differentiation and human male infertility - - TAT1/SLC26A82007 - ANR-07-JCJC-0099 - JCJC - VALID, and BLANC - La protéine TAT1 (SLC26A8), partenaire et activateur de CFTR dans le spermatozoïde, au carrefour des infertilités masculines et de la mucoviscidose. - - MUCOFERTIL2012 - ANR-12-BSV1-0011 - BLANC - VALID
Subjects: endocrine system, Flagellum, Short Report, Motility, equipment and supplies, musculoskeletal system, Annulus, Sperm, Flagelle, Mobilité, SLC26A8, Asthenozoospermia, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, cardiovascular system, Spermatozoïde, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, cardiovascular diseases, Asthénozoospermie
Abstract: The annulus is a ring-shaped structure located beneath the plasma membrane that connects the midpiece and the principal piece of mammalian sperm flagellum. It has been suggested that the annulus acts as a morphological organizer, guiding flagellum assembly during spermiogenesis, and as a diffusion barrier, confining proteins to distinct compartments of the flagellum in mature sperm. Previous studies on small cohorts of patients have attempted to correlate annulus defects with the occurrence of human asthenozoospermia. An absence of the annulus has been shown to be frequently associated with asthenozoospermia.We tried to obtain a more precise estimate of the frequency of annulus defects, by screening a large cohort of 254 men presenting asthenozoospermia (mean progressive motility of 24 %) by the immunodetection of SLC26A8, a transmembrane protein that has been shown to be specifically localized to the annulus. By contrast to previous reports, our results indicate that annulus defects are associated with asthenozoospermia in only 1.2 % of cases.We conclude that defects or an absence of the annulus are not frequently associated with asthenozoospermia. The use of annulus defects as a diagnostic endpoint in patients is therefore not appropriate.L’annulus (Anneau de Jensen) est localisé à la jonction de la pièce intermédiaire et de la pièce principale du flagelle des spermatozoïdes de mammifères. Sa fonction reste encore mal établie mais il est suggéré qu’il puisse être essentiel à l’assemblage du flagelle et à la compartimentation des protéines le long du flagelle. Des études précédentes réalisées sur des petites cohortes de sujets asthénozoospermiques ont mis en évidence des défauts fréquents de l’annulus sur les spermatozoïdes de ces sujets.Afin de mieux estimer la fréquence des défauts de l’annulus chez les sujets asthénozoospermiques, nous avons analysé une cohorte de 254 sujets asthénozoospermiques (mobilité moyenne 24 %) par immunodétection de l’annulus, en utilisant un anticorps spécifique de la protéine SLC26A8, un constituant établi de l’annulus. Nos résultats indiquent que les défauts ou absence de l’annulus ne sont retrouvés qu’à une fréquence de 1.2 %.A partir de cette étude réalisée sur le plus grand effectif de sujets asthénozoospermiques à ce jour, nous pouvons conclure que les défauts ou l’absence d’annulus ne sont pas fréquemment associés à l’asthénozoospermie modérée; l’utilisation de l’annulus comme outil de diagnostic de ce type d’asthénozoospermies, comme initialement suggéré, ne nous semble donc pas applicable.
Published: 2015
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64. États des lieux de l’innovation en santé numérique : Rapport remis à la Fondation Pour l’Avenir

Author: Dumez, Hervé, Minvielle, Etienne, Marrauld, Laurie, Centre de recherche en gestion i3 ( i3-CRG ), École polytechnique ( X ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), EA Management des Organisations de Santé ( EA MOS ), École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -PRES Sorbonne Paris Cité, Centre de recherche en gestion i3 (i3-CRG), École polytechnique (X)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), EA Management des Organisations de Santé (EA MOS), École des Hautes Études en Santé Publique [EHESP] (EHESP)-PRES Sorbonne Paris Cité, and École des Hautes Études en Santé Publique [EHESP] (EHESP)
Subjects: empowered patient, assurance, ICT, digital health, e-santé, [SHS.GESTION]Humanities and Social Sciences/Business administration, patient autonome, supply of health care, offre de soins, [ SHS.GESTION ] Humanities and Social Sciences/Business administration, insurance, NTIC
Abstract: This report reviews the main organizational, technical, structural and social trends in e-health innovation sector. It is structured around three topics: the impact of ICT in health care, the new figure of the patient and the citizen and the main trends in e-health sector. Three dynamics have been highlighted (with the caution needed in a prospective work) : the proposition of more and more integrated healthcare, a more expert and automous patient in his health’s management and the evolution of health sector toward a more preventive than curative approach. This evolution should offer a new place to personnalized and customized medicine in medical domain but also in industrial sector like insurances.; Ce rapport de recherche examine les tendances organisationnelles, techniques, structurelles et sociales de l’innovation en santé numérique. Il s’articule autour de l’approfondissement de trois axes thématiques majeurs que sont : l’impact des technologies de l’information et de la communication dans l’offre de soin, la nouvelle figure du patient et du citoyen et l’analyse des grandes tendances en santé numérique. Trois dynamiques fondamentales ont été mises en évidence (avec les réserves que peut comporter un exercice prospectif) : la proposition d’offres de soin de plus en plus intégrées, un patient plus expert et autonome dans sa santé et l’évolution du secteur vers une approche plus préventive que curative, offrant une place grandissante à la médecine personnalisée dans le domaine médical mais aussi industriel, et notamment assuranciel.
Published: 2015

65. Clonogrouping, a Rapid Multiplex PCR Method for Identification of Major Clones of Listeria monocytogenes

Author: Sylvain Brisse, Marie Touchon, Morgane Lavina, Mylène M. Maury, Marc Lecuit, Viviane Chenal-Francisque, Alexandre Leclercq, Centre National de Référence Listeria - National Reference Center Listeria (CNRL), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre collaborateur de l'OMS Listeria / WHO Collaborating Centre Listeria (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Génomique évolutive des Microbes / Microbial Evolutionary Genomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biologie des Infections - Biology of Infection, Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service des Maladies infectieuses et tropicales [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work was supported financially by the Institut Pasteur, INSERM, French Government Investissement d'Avenir grant ANR-10-LABX-62-IBEID, and Institut de Veille Sanitair, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de Référence Listeria - Biologie des Infections (CNRL), Centre collaborateur de l'OMS Listeria - Biologie des Infections (CCOMS), PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP]-Institut des Maladies Génétiques Imagine [Paris], Institut des Maladies Génétiques Imagine [Paris], and ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010)
Subjects: Microbiology (medical), Time Factors, Genotype, Epidemiology, Biology, medicine.disease_cause, MESH: Listeria monocytogenes, Microbiology, MESH: Genotype, Listeria monocytogenes, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Multiplex polymerase chain reaction, medicine, Humans, Listeriosis, MESH: Food Microbiology, MESH: Humans, MESH: Molecular Typing, MESH: Multiplex Polymerase Chain Reaction, MESH: Time Factors, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Molecular Typing, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Listeriosis, Food Microbiology, Multilocus sequence typing, Identification (biology), Multiplex Polymerase Chain Reaction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Three multiplex PCR assays were developed to identify the 11 most common Listeria monocytogenes clones in clinical and food samples; 270 (95.7%) of 282 strains of serogroups IVb, IIb, IIa, and IIc were identified accurately. This novel tool is a rapid and efficient alternative to multilocus sequence typing for identification of L. monocytogenes clones.
Published: 2015
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66. Characterization of Thymic Settling Progenitors in the Mouse Embryo Using In Vivo and In Vitro Assays

Author: Ramond, Cyrille, Bandeira, Antonio, Berthault, Claire, Pereira, Pablo, Cumano, Ana, Burlen-Defranoux, Odile, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Biologie des Populations Lymphocytaires, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: Male, T-Lymphocytes, Receptors, Antigen, T-Cell, Thymus Gland, In Vitro Techniques, Flow Cytometry, Mice, Inbred C57BL, Mice, Organ Culture Techniques, Pregnancy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Animals, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Embryonic Stem Cells, Developmental Biology
Abstract: International audience; Characterizing thymic settling progenitors is important to understand the pre-thymic stages of T cell development, essential to devise strategies for T cell replacement in lymphopenic patients. We studied thymic settling progenitors from murine embryonic day 13 and 18 thymi by two complementary in vitro and in vivo techniques, both based on the "hanging drop" method. This method allowed colonizing irradiated fetal thymic lobes with E13 and/or E18 thymic progenitors distinguished by CD45 allotypic markers and thus following their progeny. Colonization with mixed populations allows analyzing cell autonomous differences in biologic properties of the progenitors while colonization with either population removes possible competitive selective pressures. The colonized thymic lobes can also be grafted in immunodeficient male recipient mice allowing the analysis of the mature T cell progeny in vivo, such as population dynamics of the peripheral immune system and colonization of different tissues and organs. Fetal thymic organ cultures revealed that E13 progenitors developed rapidly into all mature CD3(+) cells and gave rise to the canonical γδ T cell subset, known as dendritic epithelial T cells. In comparison, E18 progenitors have a delayed differentiation and were unable to generate dendritic epithelial T cells. The monitoring of peripheral blood of thymus-grafted CD3(-/-) mice further showed that E18 thymic settling progenitors generate, with time, larger numbers of mature T cells than their E13 counterparts, a feature that could not be appreciated in the short term fetal thymic organ cultures.
Published: 2015
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67. Function of the CRISPR-Cas System of the Human Pathogen Clostridium difficile

Author: Maicol Ospina-Bedoya, Bruno Dupuy, Ekaterina Semenova, Marc Monot, Olga Soutourina, Kirill A. Datsenko, Pierre Boudry, Konstantin Severinov, Anna Lopatina, Ognjen Sekulovic, Louis-Charles Fortier, Cellule Pasteur, PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Institute of Microbiology, Rutgers, Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers)-Rutgers University System (Rutgers), Purdue University [West Lafayette], Institutes of Molecular Genetics and Gene Biology, Russian Academy of Sciences [Moscow] (RAS), Department of Microbiology and Infectious Diseases, Université de Sherbrooke [Sherbrooke], This work was supported by grants from the Institut Pasteur, University Paris Diderot, Agence Nationale de la Recherche ('CloSTARn,' ANR-13-JSV3-0005-01), Pasteur-Weizmann Council, National Institutes of Health (NIH R01 GM10407), Natural Sciences and Engineering Research Council of Canada (Discovery grant, no. 341450-2010), and Fonds de la Recherche du Québec - Santé (FRQS) (Junior 2 salary award). O.S. is an assistant professor at the University Paris Diderot. P.B. has a Ph.D. fellowship from the University Paris Diderot., ANR-13-JSV3-0005,CloSTARn,Rôle du c-di-GMP dans le contrôle via des « riboswitch » et des ARN antisens de processus cellulaires associés au comportement communautaire chez Clostridium difficile, une bactérie opportuniste responsable d'infections nosocomiales(2013), Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Université de Sherbrooke (UdeS), ANR-13-JSV3-0005,CloSTARn,Rôle du c-di-GMP dans le contrôle via des ' riboswitch ' et des ARN antisens de processus cellulaires associés au comportement communautaire chez Clostridium difficile, une bactérie opportuniste responsable d'infections nosocomiales(2013), and Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: DNA, Bacterial, MESH: CRISPR-Cas Systems, MESH: Sequence Analysis, DNA, MESH: Clostridium difficile/genetics, Molecular Sequence Data, MESH: Escherichia coli/genetics, Human pathogen, medicine.disease_cause, Microbiology, DNA sequencing, MESH: RNA, Viral/analysis, MESH: Gene Expression Profiling, 03 medical and health sciences, Plasmid, Virology, medicine, Escherichia coli, CRISPR, 030304 developmental biology, MESH: Clostridium difficile/enzymology, 0303 health sciences, MESH: Molecular Sequence Data, biology, 030306 microbiology, Clostridioides difficile, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sequence Analysis, DNA, Clostridium difficile, biology.organism_classification, QR1-502, MESH: DNA, Bacterial/genetics, 3. Good health, Gene expression profiling, RNA, Viral, MESH: RNA, Viral/genetics, CRISPR-Cas Systems, Erratum, Bacteria, Research Article
Abstract: Clostridium difficile is the cause of most frequently occurring nosocomial diarrhea worldwide. As an enteropathogen, C. difficile must be exposed to multiple exogenous genetic elements in bacteriophage-rich gut communities. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems allow bacteria to adapt to foreign genetic invaders. Our recent data revealed active expression and processing of CRISPR RNAs from multiple type I-B CRISPR arrays in C. difficile reference strain 630. Here, we demonstrate active expression of CRISPR arrays in strain R20291, an epidemic C. difficile strain. Through genome sequencing and host range analysis of several new C. difficile phages and plasmid conjugation experiments, we provide evidence of defensive function of the CRISPR-Cas system in both C. difficile strains. We further demonstrate that C. difficile Cas proteins are capable of interference in a heterologous host, Escherichia coli. These data set the stage for mechanistic and physiological analyses of CRISPR-Cas-mediated interactions of important global human pathogen with its genetic parasites., IMPORTANCE Clostridium difficile is the major cause of nosocomial infections associated with antibiotic therapy worldwide. To survive in bacteriophage-rich gut communities, enteropathogens must develop efficient systems for defense against foreign DNA elements. CRISPR-Cas systems have recently taken center stage among various anti-invader bacterial defense systems. We provide experimental evidence for the function of the C. difficile CRISPR system against plasmid DNA and bacteriophages. These data demonstrate the original features of active C. difficile CRISPR system and bring important insights into the interactions of this major enteropathogen with foreign DNA invaders during its infection cycle.
Published: 2015
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68. Entre concurrence et coopération : un 'effet bloc' des incitations réglementaires sur les relations entre établissements de santé ?

Author: Louazel, Michel, Keller, Catherine, EA Management des Organisations de Santé (EA MOS), École des Hautes Études en Santé Publique [EHESP] (EHESP)-PRES Sorbonne Paris Cité, Département des sciences humaines et sociales (SHS), École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut du droit public et de la science politique (IDPSP), Université de Rennes (UR), Centre européen de recherche et d'enseignement des géosciences de l'environnement (CEREGE), Aix Marseille Université (AMU)-Institut national des sciences de l'Univers (INSU - CNRS)-Collège de France (CdF (institution))-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Collège de France (CdF)-Institut national des sciences de l'Univers (INSU - CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), PRES Sorbonne Paris Cité-École des Hautes Études en Santé Publique [EHESP] (EHESP), EHESP, SCD, and Institut de Recherche pour le Développement (IRD)-Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Management hospitalier, [SHS.GESTION]Humanities and Social Sciences/Business administration, Etablissement hospitalier, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Concurrence entre établissements, [SHS.GESTION] Humanities and Social Sciences/Business administration, Hôpital, ComputingMilieux_MISCELLANEOUS, Relation de coopération
Abstract: International audience
Published: 2015

69. Le marketing hospitalier ; Vous avez dit marketing ? Oui, marketing !

Author: Gallopel-Morvan, Karine, Crié, Dominique, EA Management des Organisations de Santé (EA MOS), École des Hautes Études en Santé Publique [EHESP] (EHESP)-PRES Sorbonne Paris Cité, École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut du Management (IDM), Lille économie management - UMR 9221 (LEM), Université d'Artois (UA)-Université catholique de Lille (UCL)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), EA Management des Organisations de Santé ( EA MOS ), École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -PRES Sorbonne Paris Cité, École des Hautes Études en Santé Publique [EHESP] ( EHESP ), Institut du Management ( IDM ), Lille - Economie et Management ( LEM ), and Université catholique de Lille ( UCL ) -Université de Lille-Centre National de la Recherche Scientifique ( CNRS )
Subjects: Marketing, Réseau social, Management hospitalier, Communication, Utilisation service, Marketing hospitalier, Pilotage, [SHS]Humanities and Social Sciences, [ SHS ] Humanities and Social Sciences, [SHS.GESTION]Humanities and Social Sciences/Business administration, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Fidélisation du personnel, [ SHS.GESTION ] Humanities and Social Sciences/Business administration, Hôpital, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; La revue Gestions hospitalières a déjà, à de multiples reprises, ouvert ses colonnes à la question brûlante du marketing à l'hôpital. C'est donc un sujet relativement ancien que nous nous proposons d'actualiser et de revisiter. Au-delà des querelles dogmatiques qui fleurissent çà et là, nous prenons le parti d'aborder le sujet sous un angle pragmatique, c'est-à-dire au regard de la façon dont les acteurs se sont emparés du concept et de ses modes de mise en oeuvre sur le terrain. Malgré un scepticisme souvent affiché, on s'aperçoit qu'un grand nombre de structures, tout comme M. Jourdain, font du marketing sans le savoir. Or, « ce que l'on conçoit bien s'énonce clairement, disait Boileau, et les mots pour le dire arrivent aisément». Il semble donc impératif de conceptualiser au plus vite ce que pourrait être le marketing hospitalier et, comme le soulignent Laurent Tardif et Michel Louazel, « une prise de conscience et une mise en cohérence au sein de l'organisation de cette approche permettraient vraisemblablement de gagner en efficacité dans la phase de mise en oeuvre».Le sujet est de taille, les implications managériales conséquentes, nous n'en abordons qu'une toute petite partie. Même si être bien soigné reste un fondamental de la satisfaction du patient, cela ne suffit plus : le patient-client souhaite être bien accueilli, bien reçu, être consulté, informé, suivi, guidé, avoir un accès facilité aux services..., autant de facteurs qui deviennent des éléments incontournables dans la formation de sa satisfaction.En France, le champ du marketing hospitalier reste encore relativement inexploré, les pratiques assez confidentielles. Souvent, quand ils le sont, les moyens et pratiques utilisés par les différents acteurs du domaine restent ancrés dans une approche traditionnelle du marketing-management des produits, des services, des campagnes médias alors que d'autres outils plus actuels ou d'autres perspectives existent ; par exemple la perspective relationnelle ou celle, très féconde, de la création de valeur qui se développent hors du champ sanitaire. Les pays du nord de l'Europe, l'Amérique du Nord ou l'Australie sont comparativement plus avancés ; il existe par exemple dans la plupart des établissements de santé sanitaires et médico-sociaux de ces pays des directeurs ou responsables marketing.Au sommaire : - Introduction ; p. 358-360- Pourquoi et comment le marketing à l'hôpital ; p. 361-364- Projet d'établissement et marketing hospitalier ; p. 365-368- Un outil de pilotage pour les établissements de santé ; p. 370-373- La stratégie de marque : acte fondateur de la démarche d'Unicancer ; p. 374-376- L'attractivité : un enjeu marketing ; p. 377-379- Médias sociaux et communication digitale ; p. 380-384
Published: 2015

70. Distinct characteristics of endometrial and decidual macrophages and regulation of their permissivity to HIV-1 infection by SAMHD1

Author: Romain Marlin, Fabrice Chrétien, Olivier Schwartz, Héloïse Quillay, Marion Duriez, Claude Cannou, Françoise Barré-Sinoussi, Anne Lebreton, Julien Ighil, Hervé Fernandez, Marie-Thérèse Nugeyre, Hicham El Costa, Elisabeth Menu, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Régulation des Infections Rétrovirales, Institut Pasteur [Paris] (IP), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Histopathologie humaine et Modèles animaux, Centre Hospitalier Sainte-Anne, Université Paris Descartes - Paris 5 (UPD5), Service d'Obstétrique et Gynécologique [Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de gynécologie-obstétrique, médecine de la reproduction [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported by ANRS (financial support and grant 12165/13129 to H.Q. and H.E.C.), Sidaction (financial support and grant AI20-3-01671 to M.D.), the TOTAL Foundation, INSERM, and Institut Pasteur. We acknowledge the SESAME program for LSRII device funding, Institut Pasteur [Paris], Vaccine Research Institute (VRI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Institut des Maladies Emergentes et des Thérapies Innovantes ( IMETI ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Vaccine Research Institute ( VRI ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Antoine Béclère, Dpt gynécologie-obstétrique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS )
Subjects: Adult, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Inflammation, Biology, Endometrium, Microbiology, Proinflammatory cytokine, Immunophenotyping, SAM Domain and HD Domain-Containing Protein 1, Young Adult, Immune system, Antigens, CD, Virology, medicine, Humans, Monomeric GTP-Binding Proteins, [ SDV ] Life Sciences [q-bio], CD68, Macrophages, Decidua, Middle Aged, 3. Good health, Interleukin-10, Virus-Cell Interactions, Interleukin 10, medicine.anatomical_structure, Insect Science, HIV-1, Female, medicine.symptom, SAMHD1
Abstract: In order to develop strategies to prevent HIV-1 (human immunodeficiency virus type 1) transmission, it is crucial to better characterize HIV-1 target cells in the female reproductive tract (FRT) mucosae and to identify effective innate responses. Control of HIV-1 infection in the decidua (the uterine mucosa during pregnancy) can serve as a model to study natural mucosal protection. Macrophages are the main HIV-1 target cells in the decidua. Here we report that in vitro , macrophages and T cells are the main HIV-1 targets in the endometrium in nonpregnant women. As reported for decidual macrophages (dM), endometrial macrophages (eM) were found to have an M2-like phenotype (CD68 + CD163 + CD206 + IL-10 high ). However, eM and dM may belong to different subpopulations, as they differently express certain markers and secrete different amounts of proinflammatory and anti-inflammatory cytokines. We observed strong expression of the SAMHD1 restriction factor and weak expression of its inactive form (pSAMHD1, phosphorylated at residue Thr592) in both eM and dM. Infection of macrophages from both tissues was enhanced in the presence of the viral protein Vpx, suggesting a role for SAMHD1 in the restriction of HIV-1 infection. This study and further comparisons of the decidua with FRT mucosae in nonpregnant women should help to identify mechanisms of mucosal protection against HIV-1 infection. IMPORTANCE The female reproductive tract mucosae are major portals of HIV-1 entry into the body. The decidua (uterine mucosa during pregnancy) can serve as a model for studying natural mucosal protection against HIV-1 transmission. A comparison of target cells and innate responses in the decidua versus the endometrium in nonpregnant women could help to identify protective mechanisms. Here, we report for the first time that macrophages are one of the main HIV-1 target cells in the endometrium and that infection of macrophages from both the endometrium and the decidua is restricted by SAMHD1. These findings might have implications for the development of vaccines to prevent HIV-1 mucosal transmission.
Published: 2015
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71. Molecular subtypes of clear cell renal cell carcinoma are associated to sunitinib response in the metastatic setting

Author: Reza Elaidi, Virginie Verkarre, Catherine Sautès-Fridman, Gabrielle Couchy, Stéphane Oudard, Aurélien de Reyniès, Wolf H. Fridman, Etienne Becht, Jessica Zucman-Rossi, Mathilde Sibony, Nathalie Rioux-Leclercq, Sylvie Job, Alexandra Karadimou, Corinne Teghom, Jean Jacques Patard, Benoit Beuselinck, Vincent Molinié, Nicolas A. Giraldo, Arnaud Mejean, Service d'Anatomie et de Cytologie Pathologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), PremUp Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'anatomie pathologique, Hôpital Saint Joseph, Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Immunologie Cellulaire et Clinique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Service d'oncologie médicale [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Universités-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PRES Sorbonne Paris Cité-Faculté de Médecine, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Programme'Cartes d'Identité des Tumeurs ' (CIT), Ligue Nationale Contre le Cancer, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Programme'Cartes d'Identité des Tumeurs ' ( CIT ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP )
Subjects: Male, Cancer Research, Pathology, medicine.medical_specialty, Indoles, [SDV]Life Sciences [q-bio], Angiogenesis Inhibitors, Antineoplastic Agents, Gene mutation, urologic and male genital diseases, Disease-Free Survival, PBRM1, 03 medical and health sciences, 0302 clinical medicine, Renal cell carcinoma, Sunitinib, Carcinoma, medicine, Humans, Pyrroles, Carcinoma, Renal Cell, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [ SDV ] Life Sciences [q-bio], business.industry, Gene Expression Profiling, Cancer, medicine.disease, Vascular Endothelial Growth Factor Receptor-2, Kidney Neoplasms, 3. Good health, Clear cell renal cell carcinoma, Treatment Outcome, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, business, Tyrosine kinase, medicine.drug
Abstract: Purpose: Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib. Experimental Design: We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel–Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib. Results: Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands. Conclusions: ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs. Clin Cancer Res; 21(6); 1329–39. ©2015 AACR.
Published: 2015
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72. Granulomatosis with polyangiitis: endoscopic management of tracheobronchial stenosis: results from a multicentre experience

Author: Terrier, Benjamin, Dechartres, Agnès, Girard, Charlotte, Jouneau, Stéphane, Kahn, Jean-Emmanuel, Dhote, Robin, Lazaro, Estibaliz, Cabane, Jean, Papo, Thomas, Schleinitz, Nicolas, Cohen, Pascal, Begon, Edouard, Belenotti, Pauline, Chauveau, Dominique, Diot, Elisabeth, Généreau, Thierry, Hamidou, Mohamed, Hayem, Gilles, Le Guenno, Guillaume, Le Guern, Véronique, Michel, Marc, Moulis, Guillaume, Puéchal, Xavier, Rivière, Sophie, Samson, Maxime, Gonin, François, Le Jeunne, Claire, Corlieu, Pascal, Mouthon, Luc, Guillevin, Loïc, Group, French Vasculitis Study, Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Epidémiologie Clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-French Cochrane Centre, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, Service de Médecine Interne, CHU Avicenne, Service de médecine interne et maladies infectieuses, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Bichat - Claude Bernard, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital Cochin [AP-HP], Service de Médecine Interne (MARSEILLE - Med Int), Assistance Publique - Hôpitaux de Marseille (APHM), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Référence du sud-Ouest des maladies rénales rares [CHU Toulouse] (SODARE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau, Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Rhumatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Néphrologie - Médecine Interne, CHU Amiens-Picardie-hôpital Sud, Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Unité de Transplantation Pulmonaire, Hôpital Foch [Suresnes], CHU Tenon [AP-HP], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Service de médecine interne [Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Département de Néphrologie et Transplantation d'organes, Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Centre de référence des maladies rénales rares, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de médecine interne [CHU Saint-Antoine], Département de Néphrologie et Transplantation d'organes [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-French Cochrane Centre, Centre de recherches et d'études sur les droits fondamentaux ( CREDOF ), Centre de Théorie et Analyse du Droit ( CTAD ), École normale supérieure - Paris ( ENS Paris ) -École des hautes études en sciences sociales ( EHESS ) -Université Paris Nanterre ( UPN ) -Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Paris ( ENS Paris ) -École des hautes études en sciences sociales ( EHESS ) -Université Paris Nanterre ( UPN ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Laboratoire d'Immunologie ( EA 2686 ), Service de médecine interne, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), CHU Cochin [AP-HP], Service de Médecine Interne ( MARSEILLE - Med Int ), Assistance Publique - Hôpitaux de Marseille ( APHM ), Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université de Nantes ( UN ) -Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité-AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), CHU Amiens-Picardie-Hôpital Sud, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-French Cochrane Centre, Centre de recherches et d'études sur les droits fondamentaux (CREDOF), Centre de Théorie et Analyse du Droit (CTAD), Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-École normale supérieure - Paris (ENS Paris)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-École normale supérieure - Paris (ENS Paris), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité
Subjects: Male, [SDV]Life Sciences [q-bio], Constriction, Pathologic, 0302 clinical medicine, Restenosis, Prednisone, Pharmacology (medical), Cumulative incidence, Treatment Failure, 030223 otorhinolaryngology, ddc:616, Laser Therapy/methods, bronchial stenosis, Hazard ratio, Endoscopic dilatation, Middle Aged, 3. Good health, tracheobronchial involvement, Treatment Outcome, Constriction, Pathologic/etiology/therapy, subglottic stenosis, Female, Stents, Steroids, Radiology, Laser Therapy, Bronchial Diseases/etiology/therapy, Granulomatosis with polyangiitis, Tracheal Stenosis, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Subglottic stenosis, macromolecular substances, Endoscopy/methods, Injections, Granulomatosis with Polyangiitis/complications, 03 medical and health sciences, Young Adult, stomatognathic system, Steroids/administration & dosage/therapeutic use, Rheumatology, Dilatation/methods, medicine, Humans, Aged, Retrospective Studies, 030203 arthritis & rheumatology, granulomatosis with polyangiitis, [ SDV ] Life Sciences [q-bio], Tracheal Stenosis/etiology/therapy, business.industry, Retrospective cohort study, Bronchial Diseases, Endoscopy, medicine.disease, Surgery, prosthesis, business, dilatation
Abstract: International audience; OBJECTIVES: Tracheobronchial stenosis (TBS) is noted in 12-23% of patients with granulomatosis with polyangiitis (GPA), and includes subglottic stenosis and bronchial stenosis. We aimed to analyse the endoscopic management of TBS in GPA and to identify factors associated with the efficacy of endoscopic interventions. METHODS: We conducted a French nationwide retrospective study that included 47 patients with GPA-related TBS. RESULTS: Compared with patients without TBS, those with TBS were younger, more frequently female and had less frequent kidney, ocular and gastrointestinal involvement and mononeuritis multiplex. Endoscopic procedures included 137 tracheal and 50 bronchial interventions, mainly endoscopic dilatation, local steroid injection and conservative laser surgery, and less frequently stenting. After the first endoscopic procedure, the cumulative incidence of endoscopic treatment failure was 49% at 1 year, 70% at 2 years and 80% at 5 years. Factors significantly associated with a higher cumulative incidence of treatment failure were a shorter time from GPA diagnosis to endoscopic procedure [hazard ratio (HR) 1.08 (95% CI 1.01, 1.14); P = 0.01] and a bronchial stenosis [HR 1.96 (95% CI 1.28, 3.00); P = 0.002]. A prednisone dose ≥30 mg/day at the time of the procedure was associated with a lower cumulative incidence of treatment failure [HR 0.53 (95% CI 0.31, 0.89); P = 0.02]. CONCLUSION: TBS represents severe and refractory manifestations with a high rate of restenosis. High-dose systemic CSs at the time of the procedure and increased time from GPA diagnosis to bronchoscopic intervention are associated with a better event-free survival. In contrast, bronchial stenoses are associated with a higher rate of restenosis than subglottic stenosis.
Published: 2015
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73. Soluble ligands for the NKG2D receptor are released during endometriosis and correlate with disease severity

Author: Pietro Santulli, Iñaki González-Foruria, Sandrine Chouzenoux, Charles Chapron, Francisco Carmona, Frédéric Batteux, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Clinic of Gynecology, Obstetrics and Neonatology, Hospital Clínic-Institut d'Investigacions Biom è diques August Pi i Sunyer (IDIBAPS)-University of Barcelona, Service de Gynécologie Obstétrique II et Médecine de la Reproduction, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service Immunologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by grants fromUniversity Paris Descartes, INSERM, and FundaciónAlfonso Martín Escudero., Bos, Mireille, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Hospital Clínic-Institut d'Investigacions Biom è diques August Pi i Sunyer (IDIBAPS) - University of Barcelona, Université Paris Descartes - Paris 5 (UPD5) - PRES Sorbonne Paris Cité - GHU Paris Ile-de-France Ouest - CHU Cochin [AP-HP], and CHU Cochin [AP-HP]
Subjects: Adult, Science, Endometriosis, chemical and pharmacologic phenomena, GPI-Linked Proteins, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Immunity, Surgical oncology, Uterine cancer, Ascites, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Medicine, Ascitic Fluid, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Prospective Studies, 030304 developmental biology, 0303 health sciences, 030219 obstetrics & reproductive medicine, Multidisciplinary, business.industry, Histocompatibility Antigens Class I, Histology, biochemical phenomena, metabolism, and nutrition, medicine.disease, 3. Good health, Killer Cells, Natural, NK Cell Lectin-Like Receptor Subfamily K, Immunology, Intercellular Signaling Peptides and Proteins, Female, Implant, medicine.symptom, business, Research Article
Abstract: International audience; BACKGROUND:Endometriosis is a benign gynaecological disease. Abundant bulk of evidence suggests that patients with endometriosis have an immunity dysfunction that enables ectopic endometrial cells to implant and proliferate. Previous studies show that natural killer cells have a pivotal role in the immune control of endometriosis.METHODS AND FINDINGS:This is a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n= 202) during surgery for benign gynaecological conditions. After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free controls women were enrolled. Patients with endometriosis were classified according to a surgical classification in three different types of endometriosis: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE). Peritoneal fluid samples were obtained from all study participants during the surgery in order to detect soluble NKG2D ligands (MICA, MICB and ULBP-2). When samples with undetectable peritoneal fluid levels of MICA, MICB and ULBP-2 were excluded, MICA ratio levels were significantly higher in endometriosis patients than in controls (median, 1.1 pg/mg; range, 0.1-143.5 versus median, 0.6 pg/mg; range, 0.1-3.5; p=0.003). In a similar manner peritoneal fluid MICB levels were also increased in endometriosis-affected patients compared with disease-free women (median, 4.6 pg/mg; range, 1.2-4702 versus median, 3.4 pg/mg; range, 0.7-20.1; p=0.001). According to the surgical classification, peritoneal fluid soluble MICA, MICB and ULBP-2 ratio levels were significantly increased in DIE as compared to controls (p=0.015, p=0.003 and p=0.045 respectively). MICA ratio levels also correlated with dysmenorrhea (r=0.232; p=0.029), total rAFS score (r=0.221; p=0.031) and adhesions rAFS score (r=0.221; p=0.031).CONCLUSIONS:We demonstrate a significant increase of peritoneal fluid NKG2D ligands in women with endometriosis especially in those cases presenting DIE. This study suggests that NKG2D ligands shedding is a novel pathway in endometriosis complex pathogenesis that impairs NK cell function.
Published: 2015
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74. Axin1 Protects Colon Carcinogenesis by an Immune-Mediated Effect

Author: Romain Sanson, Silvia Luna Lazzara, David Cune, Caterina Luana Pitasi, Coralie Trentesaux, Marie Fraudeau, Franck Letourneur, Benjamin Saintpierre, Morgane Le Gall, Pascale Bossard, Benoit Terris, Pascal Finetti, François Bertucci, Emilie Mamessier, Béatrice Romagnolo, Christine Perret, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), PRES Sorbonne Paris Cité, Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cancer Research and Personalized Medicine - CARPEM [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and [Institut Cochin] Département Développement, Reproduction et Cancer (DRC)
Subjects: Hepatology, [SDV]Life Sciences [q-bio], Gastroenterology
Abstract: Axin1 is a negative regulator of Wnt/β-catenin signaling with tumor-suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive.We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific, Axin1-knockout mice (Axin1We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for Wnt pathway down-regulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced dextran sulfate sodium-induced colitis by attenuating the induction of a proinflammatory program. RNA-seq analyses identified an interferon γ/Th1 immune program controlled by Axin1 that enhances the inflammatory response and protects against CRC. The Axin1-dependent gene expression signature was applied to human CRC samples and identified a group of patients with potential vulnerability to immune checkpoint blockade therapies.Our study establishes, in vivo, that Axin1 has redundant function with Axin2 for Wnt down-regulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an interferon γ/Th1 program that prevents tumor growth. Linked to its T-cell-mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC.
Published: 2023
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75. Impact of prenatal diagnosis on survival of newborns with four congenital heart defects: a prospective, population-based cohort study in France (the EPICARD Study)

Author: François Goffinet, Lucile Houyel, Morgane Ballon, Babak Khoshnood, Nathalie Lelong, Jean-Marie Jouannic, Damien Bonnet, Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Chirurgical Marie Lannelongue (CCML), Centre chirurgical Marie Lannelongue, Centre de Référence des cardiopathies congénitales (M3C), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre pluridisciplinaire de diagnostic prénatal [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)
Subjects: Heart Defects, Congenital, Male, Paris, medicine.medical_specialty, Pediatrics, Population, Prenatal diagnosis, Cardiovascular Medicine, 030204 cardiovascular system & hematology, Ultrasonography, Prenatal, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pregnancy, Infant Mortality, Epidemiology, medicine, Humans, Prospective Studies, education, Tetralogy of Fallot, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, education.field_of_study, prenatal diagnosis, 030219 obstetrics & reproductive medicine, business.industry, Research, Infant, Newborn, Pregnancy Outcome, Infant, General Medicine, medicine.disease, congenital heart disease, Infant mortality, 3. Good health, Relative risk, Cohort, Female, epidemiology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Objectives(1) Assess the population-level probability of prenatal diagnosis and termination of pregnancy for fetal anomaly for four major congenital heart defects; (2) Examine, using population-based data, the relation between timing of (prenatal vs postnatal) diagnosis and risk of infant (ie, < 1 year) mortality for four major congenital heart defects (CHDs).DesignPopulation-based cohort (the EPIdémiologie des CARDiopathies congénitales) study.SettingGreater Paris area (Paris and its surrounding suburbs).PatientsThree hundred and fifty-four cases of four major CHDs, including functionally univentricular heart (FUH, N=132), d-transposition of great arteries (d-TGA, N=85), tetralogy of Fallot (TOF, N=60) and coarctation of aorta (CoA, N=77). Statistical analysis included the Mantel-Haenszel method and a test of homogeneity of risk ratios.ResultsApproximately 95% of FUH, more than two-thirds of d-TGA and TOF, and 40% of CoA were prenatally diagnosed. Overall, we did not find any statistically significant association between timing of (prenatal vs postnatal) diagnosis of CHD and risk of infant mortality (Mantel-Haenszel risk ratio 1.1, 95% CI 0.5 – 2.7); and the differences between the risk ratios of the association between prenatal diagnosis and infant mortality across the four CHDs was not statistically significant.ConclusionThese results imply that at least in the settings where specialised services are readily available, survival may no longer be the most relevant outcome, or the best criterion, for evaluating the impact of prenatal diagnosis on the outcome of CHD. The beneficial effects of prenatal diagnosis may be better sought by looking at more ’subtle' or long-term neurodevelopmental outcomes.
Published: 2017
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76. Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning

Author: Max M, Owens, Matthew D, Albaugh, Nicholas, Allgaier, Dekang, Yuan, Gabriel, Robert, Renata B, Cupertino, Philip A, Spechler, Anthony, Juliano, Sage, Hahn, Tobias, Banaschewski, Arun L W, Bokde, Sylvane, Desrivières, Herta, Flor, Antoine, Grigis, Penny, Gowland, Andreas, Heinz, Rüdiger, Brühl, Jean-Luc, Martinot, Marie-Laure Paillère, Martinot, Eric, Artiges, Frauke, Nees, Dimitri Papadopoulos, Orfanos, Herve, Lemaitre, Tomáš, Paus, Luise, Poustka, Sabina, Millenet, Juliane H, Fröhner, Michael N, Smolka, Henrik, Walter, Robert, Whelan, Scott, Mackey, Gunter, Schumann, Hugh, Garavan, Larner College of Medicine [University of Vermont, Burlington], University of Vermont [Burlington], Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Neuroimagerie: méthodes et applications (EMPENN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAL, IMAGE ET LANGAGE (IRISA-D6), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Université de Rennes (UR), Laureate Institute for Brain Research [Tulsa] (LIBR), University Hospital Mannheim | Universitätsmedizin Mannheim, Heidelberg University, Trinity College Dublin, Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Nottingham, UK (UON), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt University Of Berlin, Freie Universität Berlin, Physikalisch-Technische Bundesanstalt [Berlin] (PTB), Physikalisch-Technische Bundesanstalt [Braunschweig] (PTB), Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité), Trajectoires Développementales en Psychiatrie [Paris], Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), EPS Barthélemy Durand [Etampes], University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], University of Toronto, University Medical Center Göttingen (UMG), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Fudan University [Shanghai], IMAGEN Consortium: Tobias Banaschewski, Gareth J Barker, Arun L W Bokde, Sylvane Desrivières, Herta Flor, Antoine Grigis, Hugh Garavan, Penny Gowland, Andreas Heinz, Rüdiger Brühl, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Eric Artiges, Frauke Nees, Dimitri Papadopoulos Orfanos, Herve Lemaitre, Tomáš Paus, Luise Poustka, Sarah Hohmann, Sabina Millenet, Juliane H Fröhner, Michael N Smolka, Henrik Walter, Robert Whelan, Gunter Schumann., Medical Faculty [Mannheim], Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and robert, gabriel
Subjects: Adolescent, Substance-Related Disorders, [SDV]Life Sciences [q-bio], Bayes Theorem, Cerebral Cortical Thinning, [STAT] Statistics [stat], [SDV] Life Sciences [q-bio], [STAT]Statistics [stat], Cellular and Molecular Neuroscience, Psychiatry and Mental health, Hallucinogens, Humans, Biological Psychiatry, Cannabis
Abstract: While there is substantial evidence that cannabis use is associated with differences in human brain development, most of this evidence is correlational in nature. Bayesian causal network (BCN) modeling attempts to identify probable causal relationships in correlational data using conditional probabilities to estimate directional associations between a set of interrelated variables. In this study, we employed BCN modeling in 637 adolescents from the IMAGEN study who were cannabis naïve at age 14 to provide evidence that the accelerated prefrontal cortical thinning found previously in adolescent cannabis users by Albaugh et al. [1] is a result of cannabis use causally affecting neurodevelopment. BCNs incorporated data on cannabis use, prefrontal cortical thickness, and other factors related to both brain development and cannabis use, including demographics, psychopathology, childhood adversity, and other substance use. All BCN algorithms strongly suggested a directional relationship from adolescent cannabis use to accelerated cortical thinning. While BCN modeling alone does not prove a causal relationship, these results are consistent with a body of animal and human research suggesting that adolescent cannabis use adversely affects brain development.
Published: 2022
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77. Reporting and Methodology of Multivariable Analyses in Prognostic Observational Studies Published in 4 Anesthesiology Journals: A Methodological Descriptive Review

Author: Jean Guglielminotti, Agnès Dechartres, France Mentré, Philippe Montravers, Dan Longrois, Cedric Laouénan, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Service d'anesthésie - réanimation chirurgicale [CHU Bichat], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Epidémiologie Clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-French Cochrane Centre, Département d'épidémiologie, biostatistique et recherche clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Infection, Antimicrobiens, Modélisation, Evolution (IAME), Université Paris Diderot - Paris 7 (UPD7) - Université Paris 13 (UP13) - Université Sorbonne Paris Cité (USPC) - Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anesthésie - réanimation chirurgicale, Assistance publique - Hôpitaux de Paris (AP-HP) - AP-HP - Hôpital Bichat - Claude Bernard [Paris] - Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôtel-Dieu - Université Paris Descartes - Paris 5 (UPD5) - PRES Sorbonne Paris Cité - French Cochrane Centre, Assistance publique - Hôpitaux de Paris (AP-HP) - AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and Comets, Emmanuelle
Subjects: Publishing, medicine.medical_specialty, Multivariate analysis, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], business.industry, MEDLINE, Strengthening the reporting of observational studies in epidemiology, Missing data, Prognosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Checklist, 3. Good health, Observational Studies as Topic, Anesthesiology and Pain Medicine, Sample size determination, Anesthesiology, Family medicine, Statistics, Multivariate Analysis, medicine, Humans, Observational study, Periodicals as Topic, business
Abstract: International audience; BACKGROUND:Prognostic research studies in anesthesiology aim to identify risk factors for an outcome (explanatory studies) or calculate the risk of this outcome on the basis of patients' risk factors (predictive studies). Multivariable models express the relationship between predictors and an outcome and are used in both explanatory and predictive studies. Model development demands a strict methodology and a clear reporting to assess its reliability. In this methodological descriptive review, we critically assessed the reporting and methodology of multivariable analysis used in observational prognostic studies published in anesthesiology journals.METHODS:A systematic search was conducted on Medline through Web of Knowledge, PubMed, and journal websites to identify observational prognostic studies with multivariable analysis published in Anesthesiology, Anesthesia & Analgesia, The British Journal of Anaesthesia, and Anaesthesia in 2010 and 2011. Data were extracted by 2 independent readers. First, studies were analyzed with respect to reporting of outcomes, design, size, methods of analysis, model performance (discrimination and calibration), model validation, clinical usefulness, and STROBE (i.e., Strengthening the Reporting of Observational Studies in Epidemiology) checklist. A reporting rate was calculated on the basis of 21 items of the aforementioned points. Second, they were analyzed with respect to some predefined methodological points.RESULTS:Eighty-six studies were included: 87.2% were explanatory and 80.2% investigated a postoperative event. The reporting was fairly good, with a median reporting rate of 79% (75% in explanatory studies and 100% in predictive studies). Six items had a reporting rate
Published: 2014
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78. Development of the Sjögren's Syndrome Responder Index, a data-driven composite endpoint for assessing treatment efficacy

Author: Charles Zarnitsky, Gilles Hayem, Véronique Le Guern, Alain Saraux, Hendrika Bootsma, Valérie Devauchelle-Pensec, Xavier Puéchal, Laurent Chiche, Jean-Marie Berthelot, Pierre Yves Hatron, Aleth Perdriger, Vincent Goëb, Raphaèle Seror, Xavier Mariette, Jacques-Eric Gottenberg, Sandrine Jousse-Joulin, Divi Cornec, Petra M. Meiners, Jean Jacques Dubost, Eric Hachulla, Jacques Morel, Emmanuel Nowak, Jacques-Olivier Pers, Jean Sibilia, Arjan Vissink, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA 2216), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de rhumatologie [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Rhumatologie [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Claude Huriez [Lille], CHU Lille, Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Rhumatologie [CHU de Montpellier], CHU Montpellier, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Service de rhumatologie, Laboratoire d'Informatique Fondamentale de Lille (LIFL), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS), Service de rhumatologie [Rennes] = Rheumatology [Rennes], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies autoimmunes et systémiques rares, Department of Internal Medicine and Infectious Diseases, European Hospital, Université de Lille, Droit et Santé, Faculté de Médecine, PRES Université Lille Nord de France, Service de médecine interne, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Rhumatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Laboratoire Sols et Environnement (LSE), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Service de Rhumatologie - CH Le Havre, CH Le Havre, LabEX IGO Immunothérapie Grand Ouest, Department of Oral & Maxillofacial Surgery & Maxillofacial Prosthetics, University Medical Center Groningen and University of Groningen, Centre d'Investigation Clinique (CIC - Brest), Hôpital Sud, Service de rhumatologie [Rouen], AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-AP-HP, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Immunologie et Pathologie ( EA2216 ), Université de Brest ( UBO ) -IFR148, Immunologie des Maladies Virales et Autoimmunes ( IMVA - U1184 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Laboratoire d'Informatique Fondamentale de Lille ( LIFL ), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité-AP-HP, Laboratoire Sols et Environnement ( LSE ), Institut National de la Recherche Agronomique ( INRA ) -Université de Lorraine ( UL ), Centre d'Investigation Clinique ( CIC - Brest ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Personalized Healthcare Technology (PHT), Translational Immunology Groningen (TRIGR), Faculté de Médecine Henri Warembourg - Université de Lille, Nantes Université (Nantes Univ), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Rhumatologie - CH Le Mans, Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)
Subjects: Male, [SDV]Life Sciences [q-bio], efficacy, primary Sjogren's syndrome, DISEASE, law.invention, DOUBLE-BLIND, 0302 clinical medicine, Randomized controlled trial, law, Outcome Assessment, Health Care, Medicine, Pharmacology (medical), Fatigue, Netherlands, 0303 health sciences, Incidence, Middle Aged, primary Sjo¨gren's syndrome, 3. Good health, Sjogren's Syndrome, Treatment Outcome, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatoid arthritis, Antirheumatic Agents, Rituximab, Female, CLINICAL-TRIALS, medicine.drug, Adult, medicine.medical_specialty, Visual analogue scale, Endpoint Determination, ESSPRI, primary Sjögren’s syndrome, IMPROVEMENT, Blood Sedimentation, CONTROLLED-TRIAL, Placebo, Xerostomia, [ SDV.MHEP.RSOA ] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, outcome measures, 03 medical and health sciences, Rheumatology, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, Post-hoc analysis, Humans, 030304 developmental biology, Aged, 030203 arthritis & rheumatology, [ SDV ] Life Sciences [q-bio], business.industry, RITUXIMAB TREATMENT, Reproducibility of Results, medicine.disease, eye diseases, Infliximab, RHEUMATOID-ARTHRITIS, Surgery, Clinical trial, stomatognathic diseases, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, ESSDAI
Abstract: International audience; Objectives. To determine which outcome measures detected rituximab efficacy in the Tolerance and Efficacy of Rituximab in Sjo¨gren's Disease (TEARS) trial and to create a composite endpoint for future trials in primary SS (pSS). Methods. Post hoc analysis of the multicentre randomized placebo-controlled double-blind TEARS trial. The results were validated using data from two other randomized controlled trials in pSS, assessing rituximab (single-centre trial in the Netherlands) and infliximab, respectively. Results. Five outcome measures were improved by rituximab in the TEARS trial: patient-assessed visual analogue scale scores for fatigue, oral dryness and ocular dryness, unstimulated whole salivary flow and ESR. We combined these measures into a composite endpoint, the SS Responder Index (SSRI), and we defined an SSRI-30 response as a 530% improvement in at least two of five outcome measures. In TEARS, the proportions of patients with an SSRI-30 response in the rituximab and placebo groups at 6, 16 and 24 weeks were 47% vs 21%, 50% vs 7% and 55% vs 20%, respectively (P < 0.01 for all comparisons). SSRI-30 response rates after 12 and 24 weeks in the single-centre rituximab trial were 68% (13/19) vs 40% (4/10) and 74% (14/19) vs 40% (4/10), respectively. No significant differences in SSRI-30 response rates were found between infliximab and placebo at any of the time points in the infliximab trial. Conclusion. A core set of outcome measures used in combination suggests that rituximab could be effective and infliximab ineffective in pSS. The SSRI might prove useful as the primary outcome measure for future therapeutic trials in pSS.
Published: 2014
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79. Pleiotropic role of the RNA chaperone protein Hfq in the human pathogen Clostridium difficile

Author: Olga Soutourina, Marc Monot, Bruno Dupuy, Isabelle Martin-Verstraete, Laure Saujet, Eliane Hajnsdorf, Pierre Boudry, Joël Caillet, Céline Gracia, Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Expression Génétique Microbienne (EGM (UMR_8261 / FRE_3630)), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the Institut Pasteur, the Centre National de la Recherche Scientifique (FRE3630 and previously UPR9073), Université Paris Diderot and Agence Nationale de la Recherche (asSUPYCO, ANR-12-BSV6-0007-03, CloSTARn, ANR-13-JSV3-0005-01) and by the Initiative d'Excellence program from the French State (grant DYNAMO, ANR-11-LABX-0011). P.B. and L.S. have fellowships from the Université Paris Diderot., We thank Evelyne Couture-Tosi for performing electron microscopy analysis and M. Fujita for providing us with polyclonal anti-SigA antibodies. S.O. and I.M.-V. are assistant and full professors at the Université Paris Diderot, respectively., ANR-12-BSV6-0007,asSUPYCO,Régulation de la maturation et de la dégradation de l'ARN par les ARN antisens(2012), ANR-13-JSV3-0005,CloSTARn,Rôle du c-di-GMP dans le contrôle via des ' riboswitch ' et des ARN antisens de processus cellulaires associés au comportement communautaire chez Clostridium difficile, une bactérie opportuniste responsable d'infections nosocomiales(2013), ANR-11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes, Expression Génétique Microbienne (EGM), Institut de biologie physico-chimique (IBPC), ANR-13-JSV3-0005,CloSTARn,Rôle du c-di-GMP dans le contrôle via des « riboswitch » et des ARN antisens de processus cellulaires associés au comportement communautaire chez Clostridium difficile, une bactérie opportuniste responsable d'infections nosocomiales(2013), ANR-11-LABX-0011/11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011), and PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7)
Subjects: MESH: Signal Transduction, MESH: Clostridium difficile/metabolism, [SDV]Life Sciences [q-bio], RNA-binding protein, MESH: RNA-Binding Proteins/metabolism, MESH: Spores, Bacterial, Sigma factor, MESH: RNA-Binding Proteins/genetics, Gene expression, MESH: RNA, Antisense, MESH: Stress, Physiological, MESH: Gene Expression Regulation, Bacterial/physiology, Hfq protein, Genetics, Spores, Bacterial, MESH: Gene Expression Regulation, Bacterial, MESH: Signal Transduction/physiology, RNA-Binding Proteins, Genetic Pleiotropy, Articles, MESH: RNA, Bacterial/genetics, Clostridium difficile, RNA, Bacterial, Gene Knockdown Techniques, MESH: Molecular Chaperones, MESH: Molecular Chaperones/genetics, MESH: RNA, Bacterial, Signal Transduction, MESH: Mutation, MESH: Clostridium difficile/genetics, MESH: Genetic Pleiotropy, Biology, Microbiology, Stress, Physiological, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Antisense, Molecular Biology, Gene, MESH: Clostridium difficile, MESH: Humans, Clostridioides difficile, RNA, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Gene Expression Regulation, Bacterial, MESH: Gene Knockdown Techniques, MESH: RNA-Binding Proteins, Regulon, MESH: RNA, Bacterial/metabolism, Mutation, biology.protein, MESH: Molecular Chaperones/metabolism, Molecular Chaperones
Abstract: Clostridium difficile is an emergent human pathogen and the most common cause of nosocomial diarrhea. Our recent data strongly suggest the importance of RNA-based mechanisms for the control of gene expression in C. difficile . In an effort to understand the function of the RNA chaperone protein Hfq, we constructed and characterized an Hfq-depleted strain in C. difficile . Hfq depletion led to a growth defect, morphological changes, an increased sensitivity to stresses, and a better ability to sporulate and to form biofilms. The transcriptome analysis revealed pleiotropic effects of Hfq depletion on gene expression in C. difficile , including genes encoding proteins involved in sporulation, stress response, metabolic pathways, cell wall-associated proteins, transporters, and transcriptional regulators and genes of unknown function. Remarkably, a great number of genes of the regulon dependent on sporulation-specific sigma factor, SigK, were upregulated in the Hfq-depleted strain. The altered accumulation of several sRNAs and interaction of Hfq with selected sRNAs suggest potential involvement of Hfq in these regulatory RNA functions. Altogether, these results suggest the pleiotropic role of Hfq protein in C. difficile physiology, including processes important for the C. difficile infection cycle, and expand our knowledge of Hfq-dependent regulation in Gram-positive bacteria.
Published: 2014
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80. Molecular epidemiology of merkel cell polyomavirus: evidence for geographically related variant genotypes

Author: Antoine Gessain, Antoine Touzé, Patricia Tortevoye, Claire Martel-Jantin, Claudia Filippone, P. Coursaget, Edouard Betsem, Stéphane Descorps-Declère, Philippe V. Afonso, Nicolas Berthet, Maryse Crouzat, Olivier Cassar, Jérôme T. J. Nicol, Cellule Pasteur, PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine et des Sciences Biomédicales, Université de Yaoundé I [Yaoundé], Bioanalyse génomique (Plate-Forme), Institut Pasteur [Paris], Infectiologie Santé Publique (ISP-311), Université de Tours-Institut National de la Recherche Agronomique (INRA), Faculté des Sciences Pharmaceutiques, Université Francois Rabelais [Tours], Centre Hospitalier Territorial de Noumea, This work was financially supported by the French Government’s Investissement d’Avenir program Laboratoire d’Excellence, Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID), by the Institut Pasteur in Paris, France, by la Fondation ARC pour la Recherche sur le Cancer (A09/1/5041, 2009 and 2013), and by la Ligue Nationale contre le Cancer (RS10/75-1, RS11/75-63, and RS14/75-78)., ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Université de Yaoundé I, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)
Subjects: Male, [SDV]Life Sciences [q-bio], Merkel cell polyomavirus, Polymerase Chain Reaction, MESH: Genotype, MESH: Aged, 80 and over, Genotype, MESH: Carcinoma, Merkel Cell/epidemiology, MESH: DNA, Viral/genetics, MESH: Phylogeny, Phylogeny, Aged, 80 and over, 0303 health sciences, Molecular Epidemiology, MESH: Polyomavirus Infections/virology, MESH: Middle Aged, biology, Phylogenetic tree, Middle Aged, 3. Good health, MESH: Polymerase Chain Reaction/methods, MESH: Young Adult, Female, MESH: Carcinoma, Merkel Cell/virology, Microbiology (medical), Adult, Molecular Sequence Data, Cutaneous cancer, 03 medical and health sciences, Young Adult, MESH: Tumor Virus Infections/virology, Virology, Humans, MESH: Molecular Epidemiology, 030304 developmental biology, Polyomavirus Infections, MESH: Humans, MESH: Molecular Sequence Data, Molecular epidemiology, 030306 microbiology, MESH: Tumor Virus Infections/epidemiology, MESH: Adult, biology.organism_classification, MESH: Merkel cell polyomavirus/genetics, MESH: Male, Carcinoma, Merkel Cell, Tumor Virus Infections, DNA, Viral, MESH: Polyomavirus Infections/epidemiology, MESH: Female
Abstract: Merkel cell polyomavirus (MCPyV) is linked to a cutaneous cancer mainly occurring in Caucasians. DNA from skin swabs of 255 adults, originating from the 5 continents, were subjected to MCPyV PCRs. Phylogenetic analyses demonstrate the existence of 5 major geographically related MCPyV genotypes (Europe/North America, Africa [sub-Saharan], Oceania, South America, and Asia/Japan).
Published: 2014
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81. The SNARE Sec22b has a non-fusogenic function in plasma membrane expansion

Author: Maja Petkovic, Ignacio Izeddin, Antoine Triller, Aymen Jemaiel, Daniela Vorkel, David Tareste, Christian G. Specht, Xavier Darzacq, Jean-Marc Verbavatz, Thierry Galli, Catherine L. Jackson, Karl H Pfenninger, Frédéric Daste, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Trafic Membranaire et Morphogenèse Neuronale & Epithéliale, Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole des Neurosciences de Paris Île de France (ENP), Ecole des Neurosciences de Paris, Ecole Doctorale Frontières du Vivant - Programme Bettencourt (FdV), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Linda Crnic Institute for Down Syndrome and Department of Pediatrics, University of Colorado [Boulder], INSERM, CNRS, the Association Française contre les Myopathies (AFM), the Association pour la Recherche sur le Cancer (ARC), the Mairie de Paris Medical Research and Health Program, the Fondation pour la Recherche Médicale (FRM), the Ecole des Neurosciences de Paris (ENP), the Association Robert Debré pour la Recherche Médicale, ANR JC grant, the Ecole des Neurosciences de Paris (ENP), the Fondation des Treilles, Paris Descartes University, the PhD Program Ecole Doctorale Frontières du Vivant (FdV)--Programme Bettencourt., Institut de biologie de l'Ecole Normale Supérieure (IBENS), École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Ecole des Neurosciences de Paris Île de France ( ENP ), Ecole Doctorale Frontières du Vivant - Programme Bettencourt ( FdV ), Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité, Institut de biologie de l'Ecole Normale Supérieure ( IBENS ), École normale supérieure - Paris ( ENS Paris ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Max Planck Institute of Molecular Cell Biology and Genetics ( MPI-CBG ), Laboratoire de biologie moléculaire eucaryote du CNRS ( LBME ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, University of Colorado Boulder [Boulder], Institut de biologie de l'ENS Paris (IBENS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris
Subjects: Saccharomyces cerevisiae Proteins, Time Factors, Syntaxin 1, Gestational Age, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Endoplasmic Reticulum, Transfection, R-SNARE Proteins, 03 medical and health sciences, Mice, 0302 clinical medicine, SNAP23, Chlorocebus aethiops, Animals, Humans, Secretion, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cerebral Cortex, Neurons, 0303 health sciences, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Endoplasmic reticulum, Cell Membrane, Cell Biology, Lipid Metabolism, Membrane contact site, Cell biology, Transmembrane domain, Membrane, Animals, Newborn, COS Cells, RNA Interference, Signal transduction, Carrier Proteins, Plant lipid transfer proteins, 030217 neurology & neurosurgery, HeLa Cells, Signal Transduction
Abstract: International audience; Development of the nervous system requires extensive axonal and dendritic growth during which neurons massively increase their surface area. Here we report that the endoplasmic reticulum (ER)-resident SNARE Sec22b has a conserved non-fusogenic function in plasma membrane expansion. Sec22b is closely apposed to the plasma membrane SNARE syntaxin1. Sec22b forms a trans-SNARE complex with syntaxin1 that does not include SNAP23/25/29, and does not mediate fusion. Insertion of a long rigid linker between the SNARE and transmembrane domains of Sec22b extends the distance between the ER and plasma membrane, and impairs neurite growth but not the secretion of VSV-G. In yeast, Sec22 interacts with lipid transfer proteins, and inhibition of Sec22 leads to defects in lipid metabolism at contact sites between the ER and plasma membrane. These results suggest that close apposition of the ER and plasma membrane mediated by Sec22 and plasma membrane syntaxins generates a non-fusogenic SNARE bridge contributing to plasma membrane expansion, probably through non-vesicular lipid transfer.
Published: 2014
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82. Improving recruitment in pediatric clinical research: a strategy to consider

Author: Florentia Kaguelidou, Philippe Amiel, Claude Gaultier, Corinne Alberti, Unité de Pharmacologie Pédiatrique et Pharmacogénétique (UPPP), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche en sciences humaines et sociales (URSHS), Institut Gustave Roussy (IGR), Unité d'Épidémiologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Université Paris Diderot - Paris 7 (UPD7) - Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Robert Debré - Université Paris Diderot - Paris 7 (UPD7) - PRES Sorbonne Paris Cité
Subjects: Male, Refusal to Participate, medicine.medical_specialty, Biomedical Research, Epidemiology, business.industry, Attitude of Health Personnel, Patient Selection, Pediatrics, Clinical research, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Physicians, Medicine, Humans, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Intensive care medicine, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2014
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83. Acquiring procedural skills in ICUs: a prospective multicenter study*

Author: Jean Reignier, Alexandre Boyer, Fabrice Zeni, Damien du Cheyron, Michel Wolff, Jean-Daniel Chiche, Marie Thuong, Jean-Damien Ricard, Dominique Perrotin, Francis Schneider, Jean-Luc Diehl, Alain Combes, Guillaume Thiery, Didier Dreyfuss, Jan Hayon, Damien Roux, Laurent Papazian, Alain Mercat, Erwan L'Her, Bertrand Souweine, Gilles Bernardin, Service de Réanimation Polyvalente, CH Départemental Vendée, Service de réanimation médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), Service de réanimation-Détresses respiratoires et infections sévères, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service des Soins Intensifs [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Réanimation Médicale, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de médecine d'urgence [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Soins Intensifs [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Interactions hôte et microorganismes des épithéliums, Normandie Université (NU)-Normandie Université (NU), Optimisation continue des actions thérapeutiques par l'intégration d'informations, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service de Réanimation Médicale (CHU - BREST - Réa Med), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université de Tours (UT), Service de Réanimation Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpital Delafontaine, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation polyvalente [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Groupe de recherche sur la thrombose, pharmacologie des antithrombotiques et situations à risque (GRT), Université Jean Monnet - Saint-Étienne (UJM), Ecologie et Evolution des Microorganismes (EEM), Service de réanimation médicale [Mourier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Louis Mourier - AP-HP [Colombes], UFR médecine - Bichat, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Hôpital nord, Université Nice Sophia Antipolis (... - 2019) (UNS), Service de Réanimation Médicale [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Tours (UT)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Service de réanimation polyvalente, urgences, CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM), Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Équipe Énergie et Systèmes Embarqués (LAAS-ESE), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] (LAAS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UPS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique [Toulouse] (INP)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UPS), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique [Toulouse] (INP), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service des soins intensives, CHU Caen, Université de Tours-CHU Tours, Infection, Anti-microbiens, Modélisation, Evolution (IAME), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hopital Louis Mourier - AP-HP [Colombes], Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Équipe Énergie et Systèmes Embarqués ( LAAS-ESE ), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ), Laboratoire Microorganismes : Génome et Environnement ( LMGE ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ) -Centre National de la Recherche Scientifique ( CNRS ), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes ( URMITE ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR48, INSB-INSB-Centre National de la Recherche Scientifique ( CNRS ), CHU Angers, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -CHU Nice-Hôpital l'Archet, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHRU Brest - Service de Réanimation Médicale ( CHU - BREST - Réa Med ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Infection, Antimicrobiens, Modélisation, Evolution ( IAME ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] ( UJM ), Groupe de recherche sur la thrombose ( GRT (EA 3065) ), Université Jean Monnet [Saint-Étienne] ( UJM ), Ecologie et Evolution des Microorganismes ( EEM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hopital Louis Mourier - AP-HP [Colombes], and Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité
Subjects: Male, Inservice Training, Time Factors, medicine.medical_treatment, MESH : Prospective Studies, Critical Care and Intensive Care Medicine, 0302 clinical medicine, Risk Factors, MESH: Internship and Residency, MESH: Risk Factors, Medicine, Intubation, MESH : Female, 030212 general & internal medicine, Prospective Studies, MESH : Chest Tubes, MESH: Catheterization, Central Venous, MESH: Chest Tubes, MESH : Adult, [ SDV.MP.PRO ] Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, MESH : Risk Factors, MESH: Inservice Training, Intensive Care Units, Pneumothorax, Chest Tubes, Female, MESH : Internship and Residency, Clinical Competence, France, MESH: Clinical Competence, MESH : Intensive Care Units, MESH : Catheterization, Central Venous, Central venous catheter, MESH : Time Factors, Adult, medicine.medical_specialty, Catheterization, Central Venous, MESH : Male, MESH : Inservice Training, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, Bronchoscopies, 03 medical and health sciences, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Intubation, Intratracheal, Humans, MESH : France, Internal jugular vein, Mechanical ventilation, MESH: Humans, MESH: Intubation, Intratracheal, business.industry, MESH : Humans, MESH: Time Factors, Internship and Residency, 030208 emergency & critical care medicine, MESH: Adult, Arterial catheter, medicine.disease, MESH : Clinical Competence, MESH: Male, MESH: Prospective Studies, Surgery, Chest tube, MESH: France, Emergency medicine, MESH : Intubation, Intratracheal, MESH: Intensive Care Units, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; OBJECTIVES: Providing appropriate training of procedural skills to residents while ensuring patient safety through trainee supervision is a difficult and constant challenge. We sought to determine how effective and safe procedural skill acquisition is in French ICUs and to identify failure and complication risk factors. DESIGN: Multicenter prospective observational study. Invasive procedures performed by residents were recorded during two consecutive semesters. SETTING: Eighty-four residents. SUBJECTS: Eighty-four residents. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Number of invasive procedures performed, failure and complication rates, supervision, and assistance provided. Five thousand six hundred seventeen procedures were prospectively studied: 1,007 tracheal intubations, 1,272 arterial and 2,586 central venous catheter insertions, 457 fiberoptic bronchoscopies, and 295 chest tube insertions. During the semesters, residents performed a median of 10 intubations, 14 arterial catheter insertions, and 26 central venous catheter insertions. Complication rates were low, similar to those in the literature: 8.6% desaturation and 7.4% esophageal placement during intubation; 0.4% and 2.3% pneumothorax with jugular and subclavian central venous catheter insertions, respectively. We identified risk factors for failure and complications. Higher rates of failure and complications for intubation were associated with residents with no or little previous experience (p < 0.001); failure of internal jugular vein catheterization was associated with left-side insertion (p = 0.005) and absence of mechanical ventilation (p = 0.007). Supervision and assistance were more frequent at the beginning of the semester and for intubation and chest tube insertion. Finally, residents had less access to fiberoptic bronchoscopy and chest tube insertion. CONCLUSION: Procedural skills acquisition by residents in the ICU appears feasible and safe with complication rates comparable to what has previously been reported. We identified specific procedures and situations associated with higher failure and complication rates that could require proactive training. Questions still remain regarding minimal numbers of procedures to attain competence and how best to provide procedural training.
Published: 2014
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84. Functional analysis via standardized whole-blood stimulation systems defines the boundaries of a healthy immune response to complex stimuli

Author: Ivo Gomperts-Boneca, Ludovic Deriano, Spencer L. Shorte, Annick Dubois, Anavaj Sakuntabhai, Claude Leclerc, Caroline Demangel, Ana Cumano, Lluis Quintana-Murci, Matthew L. Albert, Antonio A. Freitas, Antoine Toubert, Lars Rogge, Manfred Schmolz, Gérard Eberl, Vincent Rouilly, Valentina Libri, Alejandra Urrutia, James P. Di Santo, Eric Tartour, Marie-Noëlle Ungeheuer, Françoise Dromer, Hugo Mouquet, Olivier Schwartz, Benoit Beitz, Mikael David, Olivier Lantz, Stéphanie Thomas, Ivo G. Boneca, Philippe Bousso, Laurent Abel, Vassili Soumelis, Cécile Delval, Darragh Duffy, Benno Schwikowski, Frédéric Tangy, Serge Hercberg, Jost Enninga, Milena Hasan, Samuel S.T. LaBrie, Sandra Pellegrini, Aurélie Bisiaux, Stanislas Pol, Marc Daëron, Andrés Alcover, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Centre d'Immunologie Humaine (CIH), Substances Lichéniques et Photoprotection, Université de Rennes (UR), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules Dendritiques, Myriad rules based medicine, Chambre Régionale d'Agriculture des Pays de la Loire, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Laboratoire de géographie physique : Environnements Quaternaires et Actuels (LGP), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Département d'Immunologie - Department of Immunology, Immunorégulation, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Laboratory of Cellular Physiology and Immunology and Chris Browne Center, Rockefeller University [New York], St. Giles Laboratory of Human Genetics of Infectious Diseases, Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Dynamiques des Réponses Immunes, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie de l'Infection - Immunobiology of Infection, Département de Génomes et Génétique - Department of Genomes and Genetics, Mycologie moléculaire, Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire (CNRMA), Microenvironnement et Immunité - Microenvironment and Immunity, Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de formation en masso-kinésithérapie (IFMK Brest), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Réponse humorale aux pathogènes, Signalisation des Cytokines - Cytokine Signaling, Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Centre de recherche sur les liens sociaux (CERLIS - UMR 8070), Université Sorbonne Nouvelle - Paris 3-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Biologie systémique - Systems Biology, Imagopole (CITECH), Laboratoire d'Immunologie Clinique, Institut Curie [Paris], Génomique virale et vaccination, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), This work benefited from support of the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01). We also acknowledge A. Pugsley for his support in obtaining funding and the logistical aspects of initiating the project, Milieu Intérieur Consortium (32 collaborateurs) : Abel L, Alcover A, Bousso P, Cumano A, Daëron M, Delval C, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Freitas A, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Pellegrini S, Pol S, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Paris 13 (UP13)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Translationnelle ( CRT ), Centre d'Immunologie Humaine ( CIH ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie et Génétique de la Paroi bactérienne, Laboratoire de géographie physique ( LGP ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Département d'Immunologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), rockefeller university, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Cellulaire des Lymphocytes, Lymphopoïèse, Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Immunobiologie de l'Infection, Département de Génomes et Génétique, Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire ( CNRMA ), Microenvironnement et Immunité, Dynamique des Interactions Hôte-Pathogène, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle ( CRESS - U1153 ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de formation en masso-kinésithérapie ( IFMK Brest ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Signalisation des Cytokines, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Génétique fonctionnelle des Maladies infectieuses, CERLIS - Centre de recherche sur les liens sociaux - UMR 8070 ( CERLIS - UMR 8070 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Sorbonne Nouvelle - Paris 3, Biologie systémique, Imagopole ( CITECH ), Institut Curie, Institut Curie-Institut Curie, Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), ANR : 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE ( 2010 ), Centre de Recherche Translationnelle (CRT), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Panthéon-Sorbonne (UP1), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and ANR: 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010)
Subjects: Chemokine, MESH : Cytokines, MESH : Antigens, Disease, MESH : Monitoring, Immunologic, Adaptive Immunity, 0302 clinical medicine, Immunophenotyping, Reference Values, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Monitoring, Immunologic, MESH: Healthy Volunteers, 0303 health sciences, MESH: Cytokines, biology, MESH: Reference Values, MESH : Immunity, Innate, Healthy Volunteers, 3. Good health, MESH: Reproducibility of Results, Infectious Diseases, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Antigens, MESH: Immunity, Innate, Inflammation Mediators, Functional analysis (psychology), Whole blood stimulation, MESH : Adaptive Immunity, Immunology, MESH: Inflammation Mediators, MESH : Reference Values, MESH : Inflammation Mediators, 03 medical and health sciences, Immune system, Immunity, Monitoring, Immunologic, Humans, Antigens, 030304 developmental biology, MESH : Healthy Volunteers, MESH: Humans, MESH : Reproducibility of Results, MESH : Humans, Reproducibility of Results, Immunity, Innate, Reference values, biology.protein, MESH: Adaptive Immunity, 030215 immunology
Abstract: International audience; Standardization of immunophenotyping procedures has become a high priority. We have developed a suite of whole-blood, syringe-based assay systems that can be used to reproducibly assess induced innate or adaptive immune responses. By eliminating preanalytical errors associated with immune monitoring, we have defined the protein signatures induced by (1) medically relevant bacteria, fungi, and viruses; (2) agonists specific for defined host sensors; (3) clinically employed cytokines; and (4) activators of T cell immunity. Our results provide an initial assessment of healthy donor reference values for induced cytokines and chemokines and we report the failure to release interleukin-1α as a common immunological phenotype. The observed naturally occurring variation of the immune response may help to explain differential susceptibility to disease or response to therapeutic intervention. The implementation of a general solution for assessment of functional immune responses will help support harmonization of clinical studies and data sharing.
Published: 2014
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85. Assessing the role of multiple pregnancies in the association between tetralogy of Fallot and assisted reproductive techniques: a path-analysis approach

Author: François Goffinet, Lucile Houyel, Karim Tararbit, Nathalie Lelong, Damien Bonnet, Babak Khoshnood, Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants ( UMR_S 953 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris-Sud - Paris 11 ( UP11 ), Chirurgie des cardiopathies congénitales, Centre chirurgical Marie Lannelongue, Centre de Référence des cardiopathies congénitales ( M3C ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Maternité Port-Royal [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], This work was supported by grants from the Agence de Biomédecine (Saint-Denis La Plaine, France) (to B.K.). The Paris Registry of Congenital Malformations received financial support from INSERM (Paris, France) and the Institut de Veille Sanitaire (Saint-Maurice, France). The EPICARD study was supported by three grants from the Ministry of Health (PHRC 2004, 2008 and 2011). Additional funding for the EPICARD study was provided by the AREMCAR Association (Association pour la Recherche et l ' Etude des Maladies Cardiovasculaires), On behalf of the EPICARD study group, Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants (UMR_S 953), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Sud - Paris 11 (UP11), Centre de Référence des cardiopathies congénitales (M3C), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Chirurgical Marie Lannelongue (CCML), and BMC, Ed.
Subjects: Adult, medicine.medical_specialty, Assi sted, Reproductive Techniques, Assisted, Reproductive techniques, Epidemiology, medicine.medical_treatment, Population, [SDV.GEN] Life Sciences [q-bio]/Genetics, Intracytoplasmic sperm injection, Cohort Studies, Young Adult, Congenital, Pregnancy, Internal medicine, Medicine, Humans, Genetics(clinical), Pharmacology (medical), education, Genetics (clinical), Tetralogy of Fallot, Medicine(all), education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Obstetrics, Research, Multiple pregnancies, Case-control study, General Medicine, medicine.disease, Endocrinology, Assisted, Case-Control Studies, Population study, Heart defects, Female, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Cohort study
Abstract: International audience; BACKGROUND: Assisted reproductive techniques (ART) are associated with a higher risk of tetralogy of Fallot (TOF) and multiple pregnancies may be associated with a higher risk of congenital anomalies. We assessed the extent to which the association between ART and risk of TOF may be mediated by the higher risk of multiple pregnancies associated with ART. METHODS: We conducted a case-control study using population-based data from the Paris Registry of Congenital Malformations for the period 1987-2009 and a cohort study of congenital heart defects (EPICARD). The study population included 395 cases of TOF and 4104 malformed controls with no known associations with ART. The analysis was based on a path-analysis model using a counterfactual approach, which allows decomposition of the total effect of ART into an indirect effect (that mediated by the association between ART and multiple pregnancies) and a direct effect. RESULTS: ART (all methods combined) were associated with a 2.6-fold higher odds of TOF after adjustment for maternal and paternal characteristics and year of birth (adjusted OR 2.6, 95%CI, 1.5-4.5). Most (79%) of the effect associated with ART was a direct effect (i.e., not mediated by multiple pregnancies), whereas 21% of the effect of ART was due to its association with multiple pregnancies (i.e., the indirect effect). In vitro fertilization with intracytoplasmic sperm injection was associated with a 3.5-fold higher odds of TOF (adjusted OR 3.5, 95%CI, 1.1-11.2); 11% of this effect was mediated through the association of ICSI with multiple pregnancies. CONCLUSIONS: By far, most of the higher risk of TOF associated with ART is a direct effect and only a small proportion of the effect may be mediated by multiple pregnancies.
Published: 2014
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86. Diagnosis of genital herpes simplex virus infection in the clinical laboratory

Author: Jérôme LeGoff, Hélène Péré, Laurent Bélec, Génétique et Ecologie des Virus, Génétique des Virus et Pathogénèse des Maladies Virales, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Microbiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, BMC, Ed., Génétique et Ecologie des Virus, Université Paris Diderot - Paris 7 (UP7) - Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Européen Georges Pompidou [APHP] (HEGP) - Université Paris Descartes - Paris 5 (UPD5) - PRES Sorbonne Paris Cité
Subjects: Viral culture, viruses, Mucocutaneous zone, Review, HSL and HSV, Biology, Herpes simplex virus, medicine.disease_cause, Virology, Asymptomatic, Genital herpes, Virus, 3. Good health, Serology, Infectious Diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology, Diagnosis, medicine, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine.symptom, Herpes Genitalis
Abstract: International audience; Since the type of herpes simplex virus (HSV) infection affects prognosis and subsequent counseling, type-specific testing to distinguish HSV-1 from HSV-2 is always recommended. Although PCR has been the diagnostic standard method for HSV infections of the central nervous system, until now viral culture has been the test of choice for HSV genital infection. However, HSV PCR, with its consistently and substantially higher rate of HSV detection, could replace viral culture as the gold standard for the diagnosis of genital herpes in people with active mucocutaneous lesions, regardless of anatomic location or viral type. Alternatively, antigen detection-an immunofluorescence test or enzyme immunoassay from samples from symptomatic patients--could be employed, but HSV type determination is of importance. Type-specific serology based on glycoprotein G should be used for detecting asymptomatic individuals but widespread screening for HSV antibodies is not recommended. In conclusion, rapid and accurate laboratory diagnosis of HSV is now become a necessity, given the difficulty in making the clinical diagnosis of HSV, the growing worldwide prevalence of genital herpes and the availability of effective antiviral therapy.
Published: 2014
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87. IN : Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms Ms no. 5311: Title : Thoracic Neoplasia-Mesothelioma Authors

Author: Jean, Didier, Le Pimpec-Barthes, F., Andujar, Pascal, Gregoire, Marc, Pairon, Jean-Claude, Scherpereel, Arnaud, Galateau-Sallé, Françoise, Jaurand, Marie-Claude, Génomique fonctionnelle des tumeurs solides (U674), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Labex Immuno-oncology [Paris] ( Université Paris Descartes - Paris 5 - PRES Sorbonne Paris Cité), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Service de Chirurgie Thoracique (Hôpital Européen Georges Pompidou [APHP] HEGP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de Pneumologie [CHI Créteil], CHI Créteil, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Biomolécules et inflammation pulmonaire, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jean, Didier
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; no abstract
Published: 2014
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88. Riboswitch Discovery by Combining RNA-Seq and Genome-Wide Identification of Transcriptional Start Sites

Author: Isabelle Rosinski-Chupin, Isabelle Martin-Verstraete, Olga Soutourina, Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), and PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Untranslated region, Riboswitch, Deep sequencing, In silico, RNA-Seq, Transcriptional start site mapping, Biology, Genome, 03 medical and health sciences, Transcription (biology), MESH: Sequence Analysis, RNA, natural sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: High-Throughput Nucleotide Sequencing, 030304 developmental biology, MESH: RNA, Messenger, Genetics, 0303 health sciences, 030306 microbiology, RNA, 5′-untranslated region, cis-Acting regulatory RNA, MESH: Bacteria, Riboswitches, MESH: 5' Untranslated Regions, MESH: Transcription Initiation Site, RNA-seq, MESH: Riboswitch
Abstract: International audience; Deep-sequencing technologies applied to RNA have tremendous potential to identify novel transcripts with single-nucleotide resolution. By combining whole-transcript cDNA sequencing (RNA-seq) and genome-wide identification of transcription start sites (dRNA-seq), it is possible to characterize long 5'-untranslated regions potentially endowed with regulatory capacities and to detect premature termination of transcription. This can be used to identify new potential riboswitches. In this chapter, we provide a detailed protocol of the dRNA-seq method based on differential pretreatment of RNAs with tobacco acid pyrophosphatase to differentiate between 5'-ends of primary and processed RNAs. We also give a briefer protocol of the preparation of RNA-seq libraries and of how to go through data bioinformatics analysis and data visualization using genome browsers. This approach is powerful to identify novel riboswitches and to demonstrate the functionality of riboswitches predicted in silico.
Published: 2014
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89. Conduites addictives chez les adolescents : Usages, prévention et accompagnement

Author: Beck, François, Dervaux, Alain, Du Roscoät, Enguerrand, Gallopel-Morvan, Karine, Grall-Bronnec, Marie, Kern, Laurence, Krebs, Marie-Odile, Legleye, Stéphane, Melchior, Maria, Naassila, Mickael, Peretti-Watel, Patrick, Dupuis, Christine, Institut National de Prévention et d'Education pour la Santé (INPES), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Parisien de Psychologie Sociale (LAPPS), Université Paris 8 Vincennes-Saint-Denis (UP8)-Université Paris Nanterre (UPN), EA Management des Organisations de Santé (EA MOS), École des Hautes Études en Santé Publique [EHESP] (EHESP)-PRES Sorbonne Paris Cité, Biostatistique, Pharmacoépidémiologie et Mesures Subjectives en Santé, PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche sur le Sport et le Mouvement (CeRSM), Université Paris Nanterre (UPN), Institut national d'études démographiques (INED), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Observatoire régional de la santé Provence-Alpes-Côte d'Azur [Marseille] (ORS PACA), Institut national de la santé et de la recherche médicale(INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), PRES Sorbonne Paris Cité-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de Recherche sur l'Alcool et les Pharmacodependances (GRAP-JE 2462), Université de Picardie Jules Verne (UPJV), and Centre de Psychiatrie et Neurosciences (U894)
Subjects: Annonces publicitaires, Internet, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Adolescent, Collection Expertise collective / ISBN 978-2-85598-912-4, Jeux vidéo, Addiction, Alcoolisme, Stupéfiants, Personnalité, Consommation d'alcool, Environnement social, Troubles mentaux, Relations familiales, Troubles cognitifs, Consommation de marijuana, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: C’est principalement à l’adolescence qu’a lieu l’initiation à l’usage de substances psychoactives dont la répétition est susceptible d’entraîner un abus voire une dépendance. En France, les niveaux de consommation des substances licites, comme l’alcool et le tabac, mais aussi illicites, comme le cannabis, demeurent élevés chez les adolescents, en dépit de la réglementation visant à limiter l’accès à ces produits et des campagnes de prévention répétées. Les conséquences sanitaires et sociales de ces consommations constituent une préoccupation de premier plan en santé publique.Sollicitée par la Mission interministérielle de lutte contre la drogue et la toxicomanie (Mildt), cette expertise collective fait le point sur les usages de substances psychoactives chez les adolescents, mais aussi sur leurs pratiques des jeux vidéo/Internet et des jeux de hasard et d’argent identifiées comme pouvant devenir problématiques. L’expertise fait également le point sur les facteurs associés à ces usages et ces pratiques, sur les dommages sanitaires et sociaux ainsi que sur les stratégies de prévention et de prise en charge des adolescents. Le groupe d’experts propose des pistes d’actions et de recherche pour améliorer la prévention de l’initiation et des usages réguliers ainsi que la prise en charge.
Published: 2014

90. Vasculature analysis of patient derived tumor xenografts using species-specific PCR assays: evidence of tumor endothelial cells and atypical VEGFA-VEGFR1/2 signalings

Author: Virginie Dangles-Marie, Eric Angevin, Sophie Vacher, Elisabetta Marangoni, Ludmilla de Plater, Fariba Nemati, Sergio Roman-Roman, Rana Hatem, Ivan Bièche, Ahmed Dahmani, Didier Decaudin, Sophie Richon, David Vallerand, Laboratoire d'Oncogénétique, CRLCC René Huguenin-Institut Curie [Paris], Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Recherche Translationnelle, Institut Curie [Paris], Service d'Oncologie, Roche SAS, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Département d'Oncologie Médicale, Centre de Recherche, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Institut Curie [Paris], This work was supported by the Comité départemental des Hauts-de-Seine de la Ligue Nationale Contre le Cancer , the Conseil régional d'Ile-de-France , the Cancéropôle Ile-de-France and the Association pour la recherche en cancérologie de Saint-Cloud (ARCS), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-PRES Sorbonne Paris Cité, BMC, Ed., CRLCC René Huguenin-INSTITUT CURIE, Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), INSTITUT CURIE, Compartimentation et dynamique cellulaires ( CDC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] ( DITEP ), Institut Gustave Roussy ( IGR ), and Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-INSTITUT CURIE
Subjects: Vascular Endothelial Growth Factor A, CD31, Cancer Research, Pathology, medicine.medical_specialty, Stromal cell, Species-specific PCR assays, Cell, Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tumor vasculature, Biomarkers, Tumor, Genetics, medicine, Animals, Humans, Autocrine signalling, Patient-deriv ed xenografts, Endothelial markers, business.industry, VEGFA-VEGFR1/2 signalings, Gene Expression Profiling, Endothelial Cells, Cancer, Neoplasms, Experimental, Endoglin, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, Bevacizumab, Gene Expression Regulation, Neoplastic, Patient-derived xenografts, Vascular endothelial growth factor A, Receptors, Vascular Endothelial Growth Factor, medicine.anatomical_structure, Oncology, Cancer cell, cardiovascular system, Female, business, Signal Transduction, Research Article
Abstract: International audience; BACKGROUND: Tumor endothelial transdifferentiation and VEGFR1/2 expression by cancer cells have been reported in glioblastoma but remain poorly documented for many other cancer types. METHODS: To characterize vasculature of patient-derived tumor xenografts (PDXs), largely used in preclinical anti-angiogenic assays, we designed here species-specific real-time quantitative RT-PCR assays. Human and mouse PECAM1/CD31, ENG/CD105, FLT1/VEGFR1, KDR/VEGFR2 and VEGFA transcripts were analyzed in a large series of 150 PDXs established from 8 different tumor types (53 colorectal, 14 ovarian, 39 breast and 15 renal cell cancers, 6 small cell and 5 non small cell lung carcinomas, 13 cutaneous melanomas and 5 glioblastomas) and in two bevacizumab-treated non small cell lung carcinomas xenografts. RESULTS: As expected, mouse cell proportion in PDXs -evaluated by quantifying expression of the housekeeping gene TBP- correlated with all mouse endothelial markers and human VEGFA RNA levels. More interestingly, we observed human PECAM1/CD31 and ENG/CD105 expression in all tumor types, with higher rate in glioblastoma and renal cancer xenografts. Human VEGFR expression profile varied widely depending on tumor types with particularly high levels of human FLT1/VEGFR1 transcripts in colon cancers and non small cell lung carcinomas, and upper levels of human KDR/VEGFR2 transcripts in non small cell lung carcinomas. Bevacizumab treatment induced significant low expression of mouse Pecam1/Cd31, Eng/Cd105, Flt1/Vegfr1 and Kdr/Vefr2 while the human PECAM1/CD31 and VEGFA were upregulated. CONCLUSIONS: Taken together, our results strongly suggest existence of human tumor endothelial cells in all tumor types tested and of both stromal and tumoral autocrine VEGFA-VEGFR1/2 signalings. These findings should be considered when evaluating molecular mechanisms of preclinical response and resistance to tumor anti-angiogenic strategies.
Published: 2014
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91. Coordination et parcours

Author: Marie-Aline Bloch, Léonie Hénaut, École des Hautes Études en Santé Publique [EHESP] (EHESP), Département des sciences humaines et sociales (SHS), EA Management des Organisations de Santé (EA MOS), PRES Sorbonne Paris Cité-École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre de sociologie des organisations (CSO), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), École des Hautes Études en Santé Publique [EHESP] (EHESP)-PRES Sorbonne Paris Cité, and Centre de sociologie des organisations (Sciences Po, CNRS) (CSO)
Subjects: 03 medical and health sciences, 0302 clinical medicine, [SHS.SOCIO]Humanities and Social Sciences/Sociology, Politiques publiques, Parcours de soins, Secteur sanitaire et social, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 030212 general & internal medicine, France, Coordination des soins, Professionnels de la coordination, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; L’accroissement du nombre de personnes âgées, handicapées ou atteintes de maladies chroniques, rend nécessaire le développement et la diversification des soins et des services, mais demande aussi une meilleure coordination des interventions. Pour lutter contre les différents cloisonnements du système de santé et d’aide, les pouvoirs publics, les professionnels et les associations de familles et d’usagers sont engagés dans un processus permanent d’innovation et de coopération à l’origine de la dynamique de l’ensemble du monde sanitaire, social et médico-social. Cet ouvrage retrace l’histoire de la structuration de la coordination en France dans plusieurs domaines d’intervention (gérontologie, santé mentale, handicap, cancer, maladies rares, accident cérébral), ainsi que l’apparition récente de la notion de parcours dans l’espace public. Il propose une analyse critique des politiques conduites en matière de coordination, et tente d’expliquer la persistance des dysfonctionnements observés. À partir d’enquêtes réalisées sur plusieurs territoires, les facteurs de succès pour la mise en place de dispositifs de coordination pérennes sont ensuite mis en évidence. L’innovation se révèle être le produit des interactions entre initiatives locales et directives nationales. Enfin, l’ouvrage propose une typologie des nouveaux professionnels de la coordination (gestionnaires de cas, pilotes, référents, médecins coordonnateurs, chargés de mission…) et souligne notamment le rôle clé joué par les cadres intermédiaires des organisations sanitaires, sociales et médico-sociales. (4e de couv.)________________________________________________________________________________________________Sommaire de l'ouvrage :La coordination dans les secteurs sanitaire, médico-social et social : l’objet de l’ouvrage. Un cadrage selon trois axes problématiques. De la coordination aux parcours: la construction d'un enjeu de santé publique. La structuration de la coordination : des histoires différentes selon les champs d’intervention. La persistance des dysfonctionnements : un essai de diagnostic. De la coordination aux parcours : un changement de paradigme. Les mots et les maux de la coordination. Sur le terrain : la dynamique des expérimentations et des coopérations. Les innovations locales à l’épreuve des politiques publiques, et réciproquement. Mettre en œuvre la coopération : un processus d’ajustement continu. De l’expérimentation au prototype : vers l’innovation intégrative. Pour une innovation solidaire. Les professionnels de la coordination: nouvelles fonctions, nouveaux défis. Trois figures de coordonnateurs interdépendants pour accompagner les personnes dans la gestion de leur parcours. De nouvelles professionnalités pour accompagner le changement. Au-delà des luttes de juridictions : une coordination distribuée. Conclusion et perspectives. Un domaine en complexité croissante. Des pistes d’amélioration pour le futur. Les limites de notre ouvrage et les perspectives de recherche.
Published: 2014
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92. Overexpression of phosphatidylinositol 4-kinase type IIIα is associated with undifferentiated status and poor prognosis of human hepatocellular carcinoma

Author: Adeodat Ilboudo, Jean-Charles Nault, Anne Corlu, Jessica Zucman-Rossi, Hélène Dubois-Pot-Schneider, Michel Samson, Jacques Le Seyec, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Labex Immuno-oncology, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This work was supported by the Institute National de la Santé et de la Recherche Médicale (INSERM), the University of Rennes 1, the Comité Grand-Ouest de la Ligue contre le Cancer, the Ligue Nationale contre le Cancer ('Cartes d'identité des tumeurs' program), IntegraGen (OSEO), HEPTROMIC (FP7), the PAIR-CHC project NoFLIC (funded by INCa and Association pour la Recherche contre le Cancer, ARC), the Réseau national CRB Foie, INCa (WntHCC) and BioIntelligence (OSEO). AI is supported by a fellowship from the Ministère de l′Education and from the ARC. JCN is supported by a grant from the INCa. HDPS is supported by grants from LIV-ES and the Contrat de Plan Etat Région (axe biothérapie)., Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), BMC, Ed., Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Génomique Fonctionnelle des Tumeurs Solides ( U1162 ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 ( UR1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Régulations des équilibres fonctionnels du foie normal et pathologique, Université de Rennes 1 ( UR1 ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Détoxication et réparation tissulaire, Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Université de Rennes 1 ( UR1 ), and Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Pathology, Cancer Research, Time Factors, Hepatocellular carcinoma, Kaplan-Meier Estimate, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Risk Factors, Surgical oncology, ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, Reverse Transcriptase Polymerase Chain Reaction, Liver Neoplasms, Cell Differentiation, Prognosis, Up-Regulation, 3. Good health, Gene Expression Regulation, Neoplastic, Phosphotransferases (Alcohol Group Acceptor), Real-time polymerase chain reaction, Oncology, Disease Progression, Biomarker (medicine), Research Article, medicine.medical_specialty, Carcinoma, Hepatocellular, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, Disease-Free Survival, Gene Expression Regulation, Enzymologic, Minor Histocompatibility Antigens, [SDV.CAN] Life Sciences [q-bio]/Cancer, Predictive Value of Tests, Cell Line, Tumor, Biomarkers, Tumor, medicine, Carcinoma, Genetics, Humans, RNA, Messenger, Proportional Hazards Models, [ SDV ] Life Sciences [q-bio], Gene Expression Profiling, Cancer, Biomarker, medicine.disease, Gene expression profiling, Multivariate Analysis, Cancer research, Neoplasm Recurrence, Local, PI4KA
Abstract: Background Hepatocellular carcinoma (HCC) is a particularly severe disease characterized by a high rate of recurrence and death even after surgical resection. Molecular characterization of HCC helps refine prognosis and may facilitate the development of improved therapy. Phosphatidylinositol 4-kinases have recently been identified as cellular factors associated with cancer. Also, phosphatidylinositol 4-kinase type IIIα (PI4KA) is necessary for the propagation of the hepatitis C virus, a major etiological factor for HCC. Methods Reverse transcription, quantitative real-time PCR was used to assay PI4KA mRNA. The expression levels were investigated both in a collection of molecularly and clinically characterized hepatic tissues from 344 patients with diverse liver diseases and in human hepatocyte cell lines whose proliferative and differentiation status was controlled by specific culture conditions. Analytical microarray data for 60 HCC and six normal liver tissue samples were exploited to study correlations between PI4KA mRNA levels and cell proliferation markers in vivo. Postoperative disease-specific survival and time to recurrence in a set of 214 patients with HCC were studied by univariate and multivariate analyses. Results PI4KA mRNA was more abundant in HCC than normal healthy tissues. This upregulation correlated significantly with both poor differentiation and the active proliferation rate in HCC. These associations were confirmed with in vitro models. Moreover, patients with HCC who had been treated by surgical resection and had higher PI4KA mRNA concentrations in their tumor tissue exhibited a higher risk of tumor recurrence (median time: 20 months versus 49 months, P = 0.0012) and shorter disease-specific survival (first quartile time: 16 months versus 48 months, P = 0.0004). Finally, the abundance of PI4KA mRNA proved to be an independent prognostic marker of survival for cases of HCC (hazard ratio = 2.36, P = 0.0064). Conclusions PI4KA mRNA could be used as a new molecular marker to improve established prognostic models for HCC. These findings also indicate possible new lines of research for the development of innovative therapeutic approaches targeting PI4KA.
Published: 2014
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93. Characterization of the SigD regulon of C. difficile and its positive control of toxin production through the regulation of tcdR

Author: Marc Monot, Johann Peltier, Martine Pestel-Caron, Jean-Louis Pons, Olga Soutourina, Imane El Meouche, Bruno Dupuy, Groupe de Recherche sur les Antimicrobiens et les Micro-Organismes (GRAM 1.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Cellule Pasteur, PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), Ecosystème intestinal, probiotiques, antibiotiques (EA 4065), Université Paris Descartes - Paris 5 (UPD5), Funding was provided by the University of Rouen., Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), Groupe de Recherche sur les Antimicrobiens et les Micro-Organismes ( GRAM 1.0 ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Pathogénèse des Bactéries Anaérobies, Institut Pasteur [Paris], Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Ecosystème intestinal, probiotiques, antibiotiques ( EA 4065 ), and Université Paris Descartes - Paris 5 ( UPD5 )
Subjects: MESH : Protein Biosynthesis, Transcription, Genetic, Mutant, lcsh:Medicine, MESH : Transcriptome, MESH : Promoter Regions, Genetic, MESH: Base Sequence, Transcription (biology), Sigma factor, Gene expression, MESH : Bacterial Proteins, MESH: Gene Silencing, lcsh:Science, Promoter Regions, Genetic, MESH : Clostridium difficile, MESH: Bacterial Proteins, MESH : Consensus Sequence, Regulation of gene expression, Genetics, 0303 health sciences, MESH: Gene Expression Regulation, Bacterial, MESH: Genetic Complementation Test, Multidisciplinary, MESH : Protein Binding, DNA-Directed RNA Polymerases, MESH : Phenotype, Phenotype, Flagella, MESH: Protein Biosynthesis, MESH: Transcription Initiation Site, Transcription Initiation Site, MESH : Mutation, Research Article, Protein Binding, MESH : Gene Expression Regulation, Bacterial, MESH: Mutation, Bacterial Toxins, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, MESH: Phenotype, MESH: Flagella, 03 medical and health sciences, Bacterial Proteins, MESH : DNA-Directed RNA Polymerases, Consensus Sequence, MESH : Gene Silencing, MESH: Promoter Regions, Genetic, Consensus sequence, Position-Specific Scoring Matrices, MESH: Protein Binding, Gene Silencing, MESH: Consensus Sequence, Gene, MESH: Clostridium difficile, 030304 developmental biology, Binding Sites, Base Sequence, MESH : Genetic Complementation Test, Clostridioides difficile, 030306 microbiology, MESH: Transcription, Genetic, MESH: Transcriptome, lcsh:R, Genetic Complementation Test, MESH : Transcription, Genetic, MESH: Position-Specific Scoring Matrices, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Gene Expression Regulation, Bacterial, MESH : Position-Specific Scoring Matrices, MESH: DNA-Directed RNA Polymerases, Regulon, MESH: Bacterial Toxins, MESH: Binding Sites, MESH : Transcription Initiation Site, Protein Biosynthesis, Mutation, MESH : Bacterial Toxins, lcsh:Q, MESH : Base Sequence, Transcriptome, MESH : Flagella, MESH : Binding Sites
Abstract: International audience; Clostridium difficile intestinal disease is mediated largely by the actions of toxins A (TcdA) and B (TcdB), whose production occurs after the initial steps of colonization involving different surface or flagellar proteins. In B. subtilis, the sigma factor SigD controls flagellar synthesis, motility, and vegetative autolysins. A homolog of SigD encoding gene is present in the C.difficile 630 genome. We constructed a sigD mutant in C. difficile 630 ∆erm to analyze the regulon of SigD using a global transcriptomic approach. A total of 103 genes were differentially expressed between the wild-type and the sigD mutant, including genes involved in motility, metabolism and regulation. In addition, the sigD mutant displayed decreased expression of genes involved in flagellar biosynthesis, and also of genes encoding TcdA and TcdB as well as TcdR, the positive regulator of the toxins. Genomic analysis and RACE-PCR experiments allowed us to characterize promoter sequences of direct target genes of SigD including tcdR and to identify the SigD consensus. We then established that SigD positively regulates toxin expression via direct control of tcdR transcription. Interestingly, the overexpression of FlgM, a putative anti-SigD factor, inhibited the positive regulation of motility and toxin synthesis by SigD. Thus, SigD appears to be the first positive regulator of the toxin synthesis in C. difficile.
Published: 2013
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94. Germline mutation in the RAD51B gene confers predisposition to breast cancer

Author: Essam Al Ageeli, André Nicolas, Grégoire Davy, Dominique Stoppa-Lyonnet, Carole Tirapo, Lisa Golmard, Xavier Sastre-Garau, Brigitte Poirot, Virginie Caux-Moncoutier, Claude Houdayer, Dorothée Michaux, Marc-Henri Stern, Laurent Castera, Catherine Dubois d'Enghien, Catherine Barbaroux, Biologie des Tumeurs, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, This work was supported by INCa Recherche Translationnelle grant number 4521000377, BMC, Ed., INSTITUT CURIE, Université Paris Descartes - Paris 5 (UPD5) - Institut Curie - Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5) - PRES Sorbonne Paris Cité, and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Cancer Research, RNA Splicing, DNA Mutational Analysis, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gene mutation, Biology, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Ovarian cancer, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, 030304 developmental biology, RAD51 paralogs, 0303 health sciences, RAD51B, Cancer, Exons, medicine.disease, Penetrance, Immunohistochemistry, 3. Good health, Pedigree, DNA-Binding Proteins, Oncology, 030220 oncology & carcinogenesis, Cancer research, RAD51C, Hereditary Breast and Ovarian Cancer Syndrome, Female, Research Article
Abstract: International audience; BACKGROUND: Most currently known breast cancer predisposition genes play a role in DNA repair by homologous recombination. Recent studies conducted on RAD51 paralogs, involved in the same DNA repair pathway, have identified rare germline mutations conferring breast and/or ovarian cancer predisposition in the RAD51C, RAD51D and XRCC2 genes. The present study analysed the five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3) to estimate their contribution to breast and ovarian cancer predisposition. METHODS: The study was conducted on 142 unrelated patients with breast and/or ovarian cancer either with early onset or with a breast/ovarian cancer family history. Patients were referred to a French family cancer clinic and had been previously tested negative for a BRCA1/2 mutation. Coding sequences of the five genes were analysed by EMMA (Enhanced Mismatch Mutation Analysis). Detected variants were characterized by Sanger sequencing analysis. RESULTS: Three splicing mutations and two likely deleterious missense variants were identified: RAD51B c.452 + 3A > G, RAD51C c.706-2A > G, RAD51C c.1026 + 5_1026 + 7del, RAD51B c.475C > T/p.Arg159Cys and XRCC3 c.448C > T/p.Arg150Cys. No RAD51D and XRCC2 gene mutations were detected. These mutations and variants were detected in families with both breast and ovarian cancers, except for the RAD51B c.475C > T/p.Arg159Cys variant that occurred in a family with 3 breast cancer cases. CONCLUSIONS: This study identified the first RAD51B mutation in a breast and ovarian cancer family and is the first report of XRCC3 mutation analysis in breast and ovarian cancer. It confirms that RAD51 paralog mutations confer breast and ovarian cancer predisposition and are rare events. In view of the low frequency of RAD51 paralog mutations, international collaboration of family cancer clinics will be required to more accurately estimate their penetrance and establish clinical guidelines in carrier individuals.
Published: 2013
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95. Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form

Author: Julie Salomon, Stanislas Lyonnet, Jean-Paul Bonnefont, Asma Smahi, Nicole Brousse, Sibylle Koletzko, Thomas Mueller, Olivier Goulet, Aurore Coulomb, Christine Bodemer, Cécile Talbotec, P. Tounian, Danielle Canioni, Virginie Colomb, Olivier Roche, Andreas R. Janecke, Arnold Munnich, Evelyne Marinier, Frank M. Ruemmele, Florence Lacaille, Jean-Pierre Hugot, Nadine Cerf-Bensussan, Jean-Louis Dufier, Julie Lemale, Françoise Poirier, Florence Campeotto, Gastroentérologie-Hépatologie et Nutrition Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions de l'épithelium intestinal et du système immunitaire (UMR_S 793), Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Assistance Publique-Hopitaux de Paris-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatric Gastroenterology, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance Publique-Hopitaux de Paris-Centre National de la Recherche Scientifique (CNRS), Service d'ophtalmologie [CHU Necker], Department of Dermatology, Department of Pediatrics I, Innsbruck Medical University [Austria] (IMU), Clinical Medical Center, Ludwig Maximilians University-Dr. von Haunersches Kinderspital, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Service de Génétique Médicale [CHU Necker], Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Recherche Agronomique (INRA), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP]-Assistance Publique-Hopitaux de Paris, Gastroentérologie et Nutrition Pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institute of Cardiometabolism and Nutrition-CHU Trousseau [APHP], Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Robert Debré Hospital-Assistance Publique-Hopitaux de Paris-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Gastro-Entérologie, Hépatologie et Nutrition pédiatriques (CHU Necker - Enfants Malades [AP-HP]), CHU Necker - Enfants Malades [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Assistance Publique-Hopitaux de Paris-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Dr. von Haunersches Kinderspital-Ludwig-Maximilians University [Munich] (LMU), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Interactions de l'épithelium intestinal et du système immunitaire ( UMR_S 793 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Recherche Agronomique ( INRA ), Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP]-Assistance Publique-Hopitaux de Paris, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institute of Cardiometabolism and Nutrition-CHU Trousseau [APHP], Service d'anatomie pathologique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité-Robert Debré Hospital-Assistance Publique-Hopitaux de Paris-Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-Assistance Publique-Hopitaux de Paris-CHU Necker - Enfants Malades [AP-HP], Innsbruck Medical University [Austria] ( IMU ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Candidate gene, Pathology, Parenteral Nutrition, medicine.disease_cause, Cohort Studies, chemistry.chemical_compound, 0302 clinical medicine, Enteropathy, 10. No inequality, Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), 0303 health sciences, Mutation, education.field_of_study, Membrane Glycoproteins, Epithelial cell adhesion molecule, Epithelial Cell Adhesion Molecule, Phenotype, Immunohistochemistry, 3. Good health, Treatment Outcome, Child, Preschool, 030211 gastroenterology & hepatology, Female, medicine.medical_specialty, Adolescent, Population, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, 03 medical and health sciences, Malabsorption Syndromes, Antigens, Neoplasm, Genetics, medicine, Humans, education, Genetic Association Studies, 030304 developmental biology, Base Sequence, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sequence Analysis, DNA, medicine.disease, Congenital tufting enteropathy, Transplantation, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Immunology, Diarrhea, Infantile, Cell Adhesion Molecules
Abstract: International audience; : Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73 %) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21 %) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (p G (abnormal splicing) was significantly associated with a better outcome (p = 0.032) with milder PN dependency to weaning in some cases. Finally, four patients (7 %) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life-threatening PN complications.
Published: 2013
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96. The Spore Differentiation Pathway in the Enteric Pathogen Clostridium difficile

Author: Marc Monot, Bruno Dupuy, Isabelle Martin-Verstraete, Olga Soutourina, Pavel V. Shelyakin, Mónica Serrano, Laure Saujet, Fátima C. Pereira, Mikhail S. Gelfand, Adriano O. Henriques, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Pathogénèse des Bactéries Anaérobies / Pathogenesis of Bacterial Anaerobes (PBA (U-Pasteur_6)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Institute for Information Transmission Problems (IITP), Russian Academy of Sciences [Moscow] (RAS), Faculty of Biengineering and Bioinformatics [Moscow], Lomonosov Moscow State University (MSU), This work was supported by grants ERA-PTG/SAU/0002/2008 (ERA-NET PathoGenoMics) to AOH and BD, and Pest-C/EQB/LA0006/2011 from the 'Fundação para a Ciência e a Tecnologia' (FCT) to AOH, FCP (SFRH/BD/45459/08) and MS (SFRH/BPD/36328/2007) were the recipient of a doctoral and a post-doctoral fellowship, respectively, from the FCT. MSG and PVS were partially supported by the Russian Academy of Sciences via program in Molecular and Cellular Biology, RFBR grant 12-04-91332 and State Contracts No. 8049 and 8283., European Project: 109584,FCT::,ERA-PTG/2008,ERA-PTG/SAU/0002/2008(2009), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7), PRES Sorbonne Paris Cité-Université Paris Diderot - Paris 7 (UPD7), and Universidade Nova de Lisboa (NOVA)
Subjects: Diarrhea, Cancer Research, lcsh:QH426-470, Transcription, Genetic, Cellular differentiation, Sigma Factor, Bacillus subtilis, Evolution, Molecular, 03 medical and health sciences, Sigma factor, Gene expression, Genetics, Humans, Promoter Regions, Genetic, Molecular Biology, Gene, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Regulation of gene expression, Spores, Bacterial, 0303 health sciences, biology, 030306 microbiology, Clostridioides difficile, fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Differentiation, Gene Expression Regulation, Bacterial, Clostridium difficile, biology.organism_classification, lcsh:Genetics, Regulon, Genome, Bacterial, Research Article, Protein Binding
Abstract: Clostridium difficile, a Gram positive, anaerobic, spore-forming bacterium is an emergent pathogen and the most common cause of nosocomial diarrhea. Although transmission of C. difficile is mediated by contamination of the gut by spores, the regulatory cascade controlling spore formation remains poorly characterized. During Bacillus subtilis sporulation, a cascade of four sigma factors, σF and σG in the forespore and σE and σK in the mother cell governs compartment-specific gene expression. In this work, we combined genome wide transcriptional analyses and promoter mapping to define the C. difficile σF, σE, σG and σK regulons. We identified about 225 genes under the control of these sigma factors: 25 in the σF regulon, 97 σE-dependent genes, 50 σG-governed genes and 56 genes under σK control. A significant fraction of genes in each regulon is of unknown function but new candidates for spore coat proteins could be proposed as being synthesized under σE or σK control and detected in a previously published spore proteome. SpoIIID of C. difficile also plays a pivotal role in the mother cell line of expression repressing the transcription of many members of the σE regulon and activating sigK expression. Global analysis of developmental gene expression under the control of these sigma factors revealed deviations from the B. subtilis model regarding the communication between mother cell and forespore in C. difficile. We showed that the expression of the σE regulon in the mother cell was not strictly under the control of σF despite the fact that the forespore product SpoIIR was required for the processing of pro-σE. In addition, the σK regulon was not controlled by σG in C. difficile in agreement with the lack of pro-σK processing. This work is one key step to obtain new insights about the diversity and evolution of the sporulation process among Firmicutes., Author Summary Clostridium difficile, a major cause of antibiotic-associated diarrhea, produces resistant spores that facilitate the persistence of this bacterium in the environment including hospitals. Its transmission is mediated by contamination of gut by spores. Understanding how this complex developmental process is regulated is fundamental to decipher C. difficile transmission and pathogenesis. The regulatory cascade controlling sporulation that involves four sigma factors, σF and σG in the forespore and σE and σK in the mother cell remains poorly characterized in C. difficile. By combining transcriptome analysis and promoter mapping, we identified genes expressed under the specific control of each sigma factor. Among sporulation-controlled proteins detected in spore, we can propose candidates for new spore coat proteins important for spore resistance. We also showed differences in the intercompartment communication between forespore and mother cell in C. difficile compared to the Bacillus subtilis model. In C. difficile, we observed that the activation of the σE regulon was partially independent of σF and that the σK regulon was not controlled by σG. Our finding suggests that the C. difficile sporulation process might be more ancestral compared to that of B. subtilis.
Published: 2013
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97. Performance of rapid diagnostic tests for imported malaria in clinical practice: results of a national multicenter study

Author: N. Godineau, Anne-Sophie Le Guern, Pascal Millet, Marie Dalichampt, Marc Thellier, Pascal Houzé, Odile Fenneteau, Isabelle Boutron, Anne Marmorat, Sandrine Houzé, Florence Tubach, Véronique Hubert, Sophie Matheron, Isabelle Poilane, Jacques Le Bras, Hélène Broutier, Stéphanie Dulucq, Christophe Choquet, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'épidémiologie Clinique [Hôtel-Dieu], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Hôtel Dieu, Hôpital Jean Verdier [AP-HP], Hôpital Delafontaine, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris] (IP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Robert Ballanger [Aulnay-sous-Bois], AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Saint-André, Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hopital Saint-Louis [AP-HP] (AP-HP), The study was supported by a grant from the French Ministry of Health (PHRC AOR06066). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Hôpital Bichat - Claude Bernard, Equipe 5 : METHODS - Méthodes de l’évaluation thérapeutique des maladies chroniques (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Sorbonne Paris Cité (USPC), Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service d'Hématologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Embedded System Lab (ESL), Thales Research and Technology, Laboratoire de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CIC epidémiologie clinique/ essais cliniques, Hôpital Bichat - Claude Bernard, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Centre National de Référence du Paludisme, AP-HP - Hôpital Bichat - Claude Bernard [Paris]-PRES Sorbonne Paris Cité-APHP, Service des maladies infectieuses et tropicales, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Sorbonne Paris Cité-APHP-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Equipe 5 : METHODS - Méthodes de l’évaluation thérapeutique des maladies chroniques ( CRESS - U1153 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Embedded System Lab ( ESL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Médical de l'Institut Pasteur, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, 030231 tropical medicine, Protozoan Proteins, lcsh:Medicine, Antigens, Protozoan, Sensitivity and Specificity, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Internal medicine, parasitic diseases, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Malaria, Falciparum, lcsh:Science, Prospective cohort study, Lactate Dehydrogenases, MESH: Protozoan Proteins, MESH: Sample Size, Imported malaria, MESH: Lactate Dehydrogenases, Multidisciplinary, MESH: Humans, biology, MESH: Malaria, Falciparum, lcsh:R, Diagnostic test, Plasmodium falciparum, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Gold standard (test), biology.organism_classification, medicine.disease, MESH: Predictive Value of Tests, MESH: Prospective Studies, MESH: Sensitivity and Specificity, 3. Good health, MESH: France, Multicenter study, Predictive value of tests, Sample Size, Immunology, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Malaria, Research Article, MESH: Antigens, Protozoan
Abstract: International audience; We compared the performance of four rapid diagnostic tests (RDTs) for imported malaria, and particularly Plasmodium falciparum infection, using thick and thin blood smears as the gold standard. All the tests are designed to detect at least one protein specific to P. falciparum (Plasmodium histidine-rich protein 2 (PfHRP2) or Plasmodium LDH (PfLDH)) and one pan-Plasmodium protein (aldolase or Plasmodium LDH (pLDH)). 1,311 consecutive patients presenting to 9 French hospitals with suspected malaria were included in this prospective study between April 2006 and September 2008. Blood smears revealed malaria parasites in 374 cases (29%). For the diagnosis of P. falciparum infection, the three tests detecting PfHRP2 showed high and similar sensitivity (96%), positive predictive value (PPV) (90%) and negative predictive value (NPV) (98%). The PfLDH test showed lower sensitivity (83%) and NPV (80%), despite good PPV (98%). For the diagnosis of non-falciparum species, the PPV and NPV of tests targeting pLDH or aldolase were 94-99% and 52-64%, respectively. PfHRP2-based RDTs are thus an acceptable alternative to routine microscopy for diagnosing P. falciparum malaria. However, as malaria may be misdiagnosed with RDTs, all negative results must be confirmed by the reference diagnostic method when clinical, biological or other factors are highly suggestive of malaria.
Published: 2013
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98. Fibrillation atriale et traitement anticoagulant: point de vue du médecin généraliste, du cardiologue et du patient [Atrial fibrillation and anticoagulation: general practitioner, cardiologist and patient's points of view]

Author: Liard, François, Le Heuzey, Jean-Yves, Aliot, Etienne, Mabo, Philippe, Leenhardt, Antoine, Institut de Recherche en Médecine Générale, IRMG, Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Cardiologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Service de Cardiologie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires, Service de cardiologie et maladies vasculaires, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], and AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité-Centre de Référence Maladies Cardiaques Héréditaires
Subjects: [ INFO.INFO-TS ] Computer Science [cs]/Signal and Image Processing, MESH : Male, MESH : Physicians, education, MESH : Aged, MESH : Prospective Studies, [ SPI.SIGNAL ] Engineering Sciences [physics]/Signal and Image processing, MESH: Anticoagulants, MESH : Patients, MESH : General Practitioners, MESH : Anticoagulants, MESH: Aged, 80 and over, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, MESH: Risk Factors, MESH: Physicians, MESH : Female, MESH : Middle Aged, [ SDV.IB ] Life Sciences [q-bio]/Bioengineering, cardiovascular diseases, MESH : Aged, 80 and over, MESH : France, MESH : Vitamin K, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: Questionnaires, MESH : Humans, MESH : Questionnaires, MESH: Vitamin K, MESH : Blood Coagulation, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH : Risk Factors, MESH : Thromboembolism, MESH: Male, MESH: Prospective Studies, MESH: General Practitioners, MESH: France, MESH : Atrial Fibrillation, MESH: Atrial Fibrillation, MESH: Patients, MESH: Thromboembolism, MESH: Blood Coagulation, [SDV.IB]Life Sciences [q-bio]/Bioengineering, MESH: Female, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing
Abstract: International audience; AIMS: This French study was set up to collect perceptions of general practitioners (GPs), cardiologists and patients on anticoagulation therapy with vitamin K antagonists (VKA) in the management of thromboembolic risk in atrial fibrillation (AF). METHOD: This is a prospective survey conducted in France, between July 1 and August 7 2011, on a sample defined to obtain a sufficient number of patient files of 133 physicians, divided into 65 cardiologists and 68 GPs. RESULTS: Three hundred and ninety-four patients on VKA and 130 patients not receiving VKA were included in this study. For more than one in three patients, AF was diagnosed incidentally in a medical consultation for another reason. In addition, 15% and 23% of diagnoses of FA were performed after hospitalization for stroke or TIA by cardiologists and GPs, respectively. According to the patient, the doctor contacted first is a GP (52% for the GP vs. 35.5% for the cardiologist), but they state that the diagnosis was made mainly by a cardiologist (63% for the cardiologist vs. 27% for the GP). In 78% of cases, cardiologists are initial prescribers. A CHADS2 score of 0 was found in 23% of patients not receiving VKA and in 11% of patients on VKA. A CHADS2 score superior or equal to 2 is significantly more frequently found in patients with paroxysmal AF. Concerning the monitoring of the patient, GPs ensure mainly monitoring of INR. In terms of compliance, according to doctors, their patients systematically take their treatment in 91% of cases. However, by interviewing patients, 60% of non-compliant patients are considered compliant by their physician. CONCLUSION: This study has achieved an overview of anticoagulation treatment in AF, in France. The initiation is mainly ensured by the cardiologist and the monitoring by the GP. Assessments between cardiologists and GPs are relatively similar, however, it appears that anticoagulation treatment is under-prescribed for the patients at risk.
Published: 2013
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99. Rapid-antigen detection tests for group a streptococcal pharyngitis: revisiting false-positive results using polymerase chain reaction testing

Author: Philippe Bidet, Patrice Deberdt, Patricia Mariani-Kurkdjian, Camille d’Humières, Jérémie F. Cohen, Sandrine Liguori, Robert M. Cohen, Corinne Levy, Franck Thollot, Edouard Bingen, François Corrard, Martin Chalumeau, Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants (UMR_S 953), Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Etudes cliniques et épidémiologiques, la recherche diagnostique et thérapeutique en pathologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Association Clinique Thérapeutique Infantile du Val de Marne (ACTIV), Service de Microbiologie [Créteil], CHI Créteil, AP-HP Hôpital universitaire Robert-Debré [Paris], Centre de Recherche Clinique [Créteil] (CRC), Centre Hospitalier Intercommunal de Créteil (CHIC), Association Française de P ediatrie Ambulatoire (AFPA), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-CH de Troyes, Recherche Epidémiologique en Santé Périnatale et Santé des Femmes et des Enfants ( UMR_S 953 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris-Sud - Paris 11 ( UP11 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Association Clinique Thérapeutique Infantile du Val de Marne (ACTIV), Service de Microbiologie [R Debré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Centre de Recherche Clinique ( CRC ), Association Française de P ediatrie Ambulatoire ( AFPA ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -CH de Troyes, and Debs, Nayla
Subjects: MESH : Streptococcal Infections, MESH: Pharynx, MESH : Child, Preschool, medicine.disease_cause, Polymerase Chain Reaction, Group A, law.invention, 0302 clinical medicine, MESH : Child, MESH: Streptococcal Infections, law, MESH: Child, MESH: Staphylococcus aureus, 030212 general & internal medicine, Child, MESH : Polymerase Chain Reaction, Polymerase chain reaction, Polymerase, 0303 health sciences, biology, MESH : Staphylococcus aureus, MESH : Antigens, Bacterial, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Pharyngitis, MESH: Case-Control Studies, 3. Good health, Streptococcal pyrogenic exotoxin B, Staphylococcus aureus, Child, Preschool, MESH : Streptococcus pyogenes, MESH : Sensitivity and Specificity, medicine.symptom, Bacterial inhibition, MESH: Streptococcus pyogenes, psychological phenomena and processes, MESH : Case-Control Studies, Adolescent, Streptococcus pyogenes, MESH : Pharynx, Sensitivity and Specificity, Microbiology, 03 medical and health sciences, Antigen, MESH : Adolescent, Streptococcal Infections, mental disorders, medicine, Humans, False Positive Reactions, MESH: Adolescent, Antigens, Bacterial, MESH: Humans, MESH: False Positive Reactions, 030306 microbiology, business.industry, MESH: Pharyngitis, MESH : Humans, MESH : Pharyngitis, MESH: Child, Preschool, MESH: Polymerase Chain Reaction, Virology, MESH: Sensitivity and Specificity, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, MESH : False Positive Reactions, Pediatrics, Perinatology and Child Health, biology.protein, Pharynx, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Antigens, Bacterial
Abstract: International audience; We investigated mechanisms of the false-positive test results on rapid-antigen detection test (RADT) for group A Streptococcal (GAS) pharyngitis. Most RADT false-positives (76%) were associated with polymerase chain reaction-positive GAS results, suggesting that RADT specificity could be considered close to 100%. Finding that 61% of GAS culture-negative but RADT-positive cases were positive on both GAS polymerase chain reaction and Staphylococcus aureus testing, we posit bacterial inhibition as causative.
Published: 2013
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100. Recombinant human activated protein C for adults with septic shock

Author: Annane, Djillali, Timsit, Jean-François, Mégarbane, Bruno, Martin, Claude, Misset, Benoit, Mourvillier, Bruno, Siami, Shidasp, Chagnon, Jean-Luc, Constantin, Jean-Michel, Petitpas, Franck, Souweine, Bertrand, Amathieu, Roland, Forceville, Xavier, Charpentier, Claire, Tesnière, Antoine, Chastre, Jean, Bohe, Julien, Colin, Gwenhael, Cariou, Alain, Renault, Alain, Brun-Buisson, Christian, Bellissant, Eric, Laboratoire d'étude de la réponse neuroendocrine au Sepsis (LARENES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique (NAVVEC - UM 81 (UMR 8206/ U705)), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Diderot - Paris 7 (UPD7), Service Anesthésie et Réanimation [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Radiologie et Imagerie Médicale, Hôpital Saint-Joseph, Service de Réanimation Polyvalente, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-Faculté de Médecine, Service de réanimation médicale et infectieuse, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anesthésie-Réanimation, Centre Hospitalier d'Etampes, Centre Hospitalier de Valenciennes, Service d'Anésthésie Réanimation [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Réanimation Chirurgicale, Hôpital de La Milétrie, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), Service d'Anesthésie Réanimation, Hôpital Jean Verdier [AP-HP], Réanimation, CH Meaux, Service de Réanimation Chirurgicale [CHRU Nancy], Hôpital Cochin [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Réanimation Médicale Sud, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Réanimation, Centre Hospitalier René Dubos [Pontoise], Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité d’Investigation Neurologique [CHU Rennes] (CIC-P 0203 INSERM), CHU Pontchaillou [Rennes]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut des Neurosciences Cliniques de Rennes (INCR), Service de réanimation médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Paris Diderot - Paris 7 (UPD7)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Pontchaillou [Rennes]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR), Réanimation médico-chirurgicale et EA4342, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique ( NAVVEC (UM 81) ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital Nord [CHU - APHM], Université Paris Descartes - Paris 5 ( UPD5 ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Département anesthésie et réanimation, CHU Clermont-Ferrand-Hôpital d'Estaing, Laboratoire Microorganismes : Génome et Environnement ( LMGE ), Université Blaise Pascal - Clermont-Ferrand 2 ( UBP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université d'Auvergne - Clermont-Ferrand I ( UdA ), Hôpital Jean Verdier, CHU Cochin [AP-HP], Reanimation Medicale, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Department of Clinical Pharmacology, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Rationale: A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate. Objectives: The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock. Methods: This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 μg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90. Measurements and Main Results: On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events. Conclusions: In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Clinical trial registered with www.clinicaltrials.gov (NCT00625209).
Published: 2013
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